Potential ADHD Genes based on Ma'ayan Lab's ARCHS4 Data - Assistance from ChatGPT
Potential ADHD Genes Based On Ma'ayan Lab's ARCHS4 Data - Assistance From ChatGPT
Introduction to Gene Information for ADHD
Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex neurodevelopmental condition influenced by a combination of genetic, environmental, and neurological factors. Recent advancements in genomics have enabled researchers to identify specific genes and pathways that may contribute to the symptoms and traits associated with ADHD, such as inattention, impulsivity, and emotional dysregulation.
This blog post explores detailed information about key ADHD-related genes derived from the ARCHS4 database, which provides insights into gene expression, biological processes, pathways, and tissue-specific activity. By analyzing this data, we can better understand how these genes influence neural and behavioral functions, shedding light on the biological underpinnings of ADHD.
The genes examined include ADGRL1, SGSM2, ADGRL3, TMEM30A, MC4R, NUAK1, and DRD4. Each gene has been evaluated for its role in ADHD-relevant processes such as synaptic plasticity, neurotransmitter signaling, and motor coordination. Additionally, their expression in critical brain regions, such as the cerebral cortex and hypothalamus, underscores their significance in ADHD research.
This analysis not only highlights the complexity of ADHD but also emphasizes the importance of integrating genetic data into our understanding of its symptoms and potential treatment strategies.
I included gene descriptions and my variants. I included Varsome pages for only the potential disease-causing variants with the focus on Meta Scores. These variants are potential indicators for my Ataxia which has genetic overlap with ADHD and other neurodivergent conditions as well as mental illnesses. I am a neurodivergent with Dyslexia, Dyspraxia, ADHD. Like Ataxia, Dyspraxia has to do with problems with coordination. I included frequencies for all databases that have genomes that possess the variant. I provided Integrative Genomic Viewer (IGV) BAM screenshots for each variant and provided IGV VCF for all of the variants separated by gene.
I included the variants' Combined Annotation Dependent Depletion (CADD) scores. CADD is a tool for scoring the deleteriousness of single nucleotide variants, multi-nucleotide substitutions as well as insertion/deletions variants in the human genome. It is a framework that integrates multiple annotations into one metric by contrasting variants that survived natural selection with simulated mutations. Variants at the 10th-% of CADD scores are assigned to CADD-10, top 1% to CADD-20, top 0.1% to CADD-30, etc. The results of this transformation are the "scaled" CADD scores.
I included Variant Effect Predictor (VEP) analyses for the variants.
What is Ma'ayan Lab's ARCHS4?
Ma'ayan Lab's ARCHS4 (All RNA-seq and ChIP-seq Signatures for Functional Genomics) is a comprehensive database that integrates publicly available RNA sequencing (RNA-Seq) data to provide insights into gene expression across various tissues, cell types, and conditions. ARCHS4 leverages data from thousands of RNA-Seq experiments to help researchers explore gene activity, predict biological processes, and identify tissue-specific expression patterns.
How ARCHS4 Helps in Understanding Genes and ADHD
1. Gene Expression Data:
ARCHS4 provides normalized gene expression scores for tissues and cell types, allowing researchers to determine where a gene is active. For ADHD-related genes, this data highlights their roles in critical brain regions like the cerebral cortex, hypothalamus, and cerebellum.
2. Biological Process Predictions:
Using Gene Ontology (GO) terms, ARCHS4 predicts the biological processes in which a gene is involved, such as synaptic transmission, neurotransmitter signaling, and locomotory behavior. These processes are essential for understanding ADHD-related traits like impulsivity and hyperactivity.
3. Pathway Analysis:
ARCHS4 links genes to biological pathways, such as dopaminergic synapse signaling and circadian entrainment, that are highly relevant to ADHD. These connections help identify how genes interact in larger networks affecting behavior and cognition.
4. Tissue-Specific Expression:
Tissue expression data in ARCHS4 provides insights into where genes are most active. For ADHD, this includes the central nervous system (e.g., cerebral cortex, midbrain, and hypothalamus), as well as other regions like the retina and parasympathetic nervous system.
5. User-Friendly Access:
ARCHS4 is designed with researchers in mind, providing tools for easy access to large-scale gene expression data. It empowers researchers to quickly identify the most relevant genes and pathways for their area of interest.
Relevance to ADHD Research
ARCHS4's data-driven approach allows for an in-depth exploration of how specific genes contribute to ADHD. By integrating expression data with biological processes and pathways, it provides a clearer picture of the molecular mechanisms underlying ADHD. This information is invaluable for identifying potential therapeutic targets and advancing our understanding of the genetic basis of the disorder.
ARCHS4 Z-Scores
What are Z-Scores in ARCHS4?
Z-scores in ARCHS4 are statistical measures that indicate how significantly a gene is expressed in a given tissue, cell type, or biological process compared to the average expression level across all datasets. They represent how many standard deviations a gene's expression level deviates from the mean.
How Z-Scores are Used in ARCHS4:
1. Gene-Tissue Expression:
Z-scores help identify tissues or cell types where a gene is significantly over- or under-expressed.
High positive Z-scores (>2.0): Indicate significant overexpression of the gene in a particular tissue or process.
Low Z-scores (<-2.0): Suggest the gene is significantly under-expressed or inactive in that tissue.
Example:
If ADGRL1 has a Z-score of 11.4 in the hypothalamus, it indicates highly enriched expression in this brain region, making it relevant to ADHD-related functions like emotional regulation and attention.
2. Gene Ontology (GO) Enrichment:
ARCHS4 uses Z-scores to predict involvement in specific biological processes, such as neurotransmitter transport or synaptic plasticity.
Higher Z-scores indicate stronger associations between the gene and the process.
3. Pathway Analysis:
Z-scores rank pathways based on how significantly a gene or group of genes is associated with them. This allows researchers to identify key signaling networks relevant to disorders like ADHD.
Thresholds for Significance:
Z-Score > 2.0: Indicates significant overexpression or involvement.
Z-Score < -2.0: Indicates significant under-expression or exclusion.
Z-Scores near 0: Indicate no significant deviation from the mean.
Why Z-Scores Matter for ADHD Research:
In the context of ADHD, Z-scores from ARCHS4 highlight:
Genes with strong expression in ADHD-relevant brain regions (e.g., prefrontal cortex, hypothalamus).
Biological processes that are dysregulated in ADHD, such as dopamine receptor signaling or synaptic transmission.
Pathways that contribute to ADHD traits like impulsivity, hyperactivity, and attention deficits.
ARCHS4’s Z-scores enable researchers to prioritize the most biologically relevant genes and processes, guiding targeted research and therapeutic exploration.
ADGRL1 (Adhesion G Protein-Coupled Receptor L1)
Definition:
ADGRL1 encodes a member of the adhesion G-protein-coupled receptor (GPCR) family, which plays a role in synaptic adhesion, neuronal communication, and the development of neural networks.
Relevance to ADHD:
ADGRL1 is highly expressed in ADHD-relevant brain regions (e.g., hypothalamus, cerebral cortex) and is involved in processes like synaptic plasticity and neurotransmitter signaling. Variants in this gene may disrupt neuronal connectivity and contribute to ADHD-related traits like impulsivity and inattention.
My ADGRL1 Variants
1. One Upstream/Promoter Variant:
Definition: This variant is located in the promoter region upstream of ADGRL1. They specifically impact the regulatory DNA sequences that control the start and rate of gene transcription.
Relevance to ADHD: Changes in promoter activity caused by this variant could result in increased or decreased expression of ADGRL1, affecting neuronal communication and synaptic plasticity—both of which are linked to cognitive and behavioral symptoms in ADHD.
NC_000019.10:g.14206950C>A 19-14206950-C-A
rs553841438
0.001256 (191/152074, GnomAD)
0.001462 (387/264690, TOPMED)
0.00093 (13/14050, ALFA)
0.0006 (4/6404, 1000G_30x)
0.0008 (4/5008, 1000G)
0.5 (1/2, SGDP_PRJ)
0.001023 (848/829074, AllofUs)
CADD: 16.5
.png)
2. One Upstream Variant
Definition: This variant is located upstream of the ADGRL1 gene, where it may influence gene regulation by affecting elements that control transcription. Upstream variants can impact gene expression depending on their proximity to regulatory regions and interactions with enhancers or silencers.
Relevance to ADHD: ADGRL1 plays a crucial role in synaptic adhesion and neurotransmitter regulation, both essential for attention, impulse control, and cognitive processing. Changes in ADGRL1 expression could influence neural connectivity and communication, contributing to ADHD-related traits.
NC_000019.10:g.14206738G>T 19-14206738-G-T
rs936691780
0.002433 (357/146710, GnomAD)
0.00049 (9/18456, ALFA)
0.0019 (12/6404, 1000G_30x)
0.002 (1/600, NorthernSweden)
0.5 (1/2, SGDP_PRJ)
0.002013 (1665/827050, AllofUs)
CADD: 12.5
.png)
https://maayanlab.cloud/archs4/gene/ADGRL1
https://maayanlab.cloud/Enrichr/#find!gene=ADGRL1
https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADGRL1
https://www.proteinatlas.org/ENSG00000072071-ADGRL1
https://neurodivergence.blogspot.com/2024/06/my-attention-deficit-hyperactivity.html
https://pmc.ncbi.nlm.nih.gov/articles/PMC9388395/
https://pmc.ncbi.nlm.nih.gov/articles/PMC6137404/
SGSM2 (Small GTPase Signaling Modulator 2)
Definition:
SGSM2 is involved in modulating small GTPase activity, which regulates intracellular signaling pathways, including those related to neuronal communication and vesicle transport.
Relevance to ADHD:
SGSM2 participates in neurotransmitter transport, synaptic plasticity, and locomotion-related processes. Its broad expression in CNS tissues highlights its importance in neural signaling, with potential links to ADHD symptoms like hyperactivity and coordination challenges.
My SGSM2 Variants
1. Nonsense-Mediated Decay (NMD)-Escaping Stop Gained/Noncoding Transcript Exonic/Downstream Variant:
Definition: This variant introduces a premature stop codon in the SGSM2 gene but escapes nonsense-mediated decay (NMD), meaning the transcript is not degraded as it normally would be. It occurs in a noncoding transcript, specifically in an exon, and is classified as a downstream variant due to its proximity to the gene's end. Additionally, this transcript has a retained intron biotype, meaning an intron that is usually removed remains within the final transcript, potentially altering its function.
Relevance to ADHD: A stop-gained variant that escapes NMD could result in a truncated protein that either retains partial function or acquires new, potentially disruptive functions. The presence of a retained intron may further affect RNA stability, splicing, or translation efficiency, leading to impaired neurotransmitter regulation and synaptic plasticity. Since SGSM2 is involved in intracellular signaling and neurotransmitter transport, disruptions in its function could contribute to ADHD-related traits like hyperactivity, impulsivity, and cognitive dysregulation.
NC_000017.11:g.2379146C>T 17-2379146-C-T
rs867998099
0.000001859 (3/1614054, GnomAD)
0.000008 (2/264690, TOPMED)
0.00006 (1/16760, 8.3KJPN)
0.0005 (1/1832, Korea1K)
0.000006 (5/829648, AllofUs)
2. Missense/Synonymous-NMD/Upstream-Downstream Transcript Variant
Definition: This variant results in a missense mutation in the SGSM2 gene, causing a single amino acid change in the protein. While shown as potentially benign by in-silico predictors, it is also associated with multiple regulatory transcript effects, including a synonymous variant in an NMD (Nonsense-Mediated Decay) transcript, two downstream transcript variants (one of which is NMD-sensitive), and three upstream transcript variants (two of which contain retained introns). The NMD-associated transcripts may be unstable and targeted for degradation, while the retained intron transcripts may affect RNA processing and splicing, potentially leading to altered gene expression.
Relevance to ADHD: Although the missense variant itself is not predicted to have a major functional impact, the combined effect of transcript-level variations could still influence SGSM2 expression and function. NMD-mediated degradation could reduce overall SGSM2 levels, while retained introns may impact RNA stability and protein production. Since SGSM2 is involved in neurotransmitter transport and intracellular signaling, these disruptions may affect dopamine and glutamate pathways, potentially influencing synaptic plasticity, attention regulation, impulsivity, and cognitive processing—all traits commonly associated with ADHD.
NC_000017.11:g.2363087G>T 17-2363087-G-T
rs112097002
0.0002207 (356/1613210, GnomAD)
0.000175 (32/183026, ALFA)
0.000442 (46/104144, ExAC)
0.00225 (177/78610, PAGE_STUDY)
0.00161 (21/13006, GO-ESP)
0.0020 (13/6404, 1000G_30x)
0.0024 (12/5008, 1000G)
0.5 (1/2, SGDP_PRJ)
0.000984 (816/829648, AllofUs)
.png)
https://maayanlab.cloud/archs4/gene/SGSM2
https://maayanlab.cloud/Enrichr/#find!gene=SGSM2
https://www.genecards.org/cgi-bin/carddisp.pl?gene=SGSM2
https://www.proteinatlas.org/ENSG00000141258-SGSM2
https://neurodivergence.blogspot.com/2024/03/my-rare-single-nucleotide-variants-that.html
ADGRL3 (Adhesion G Protein-Coupled Receptor L3)
Definition:
ADGRL3 is another member of the adhesion GPCR family, involved in synaptic development, neural circuit formation, and neurotransmitter regulation.
Relevance to ADHD:
ADGRL3 is implicated in locomotory behavior, synaptic transmission, and dopamine receptor signaling. Its high expression in regions like the cerebellum and cerebral cortex suggests a key role in motor control and cognitive functions, both of which are affected in ADHD.
My ADGRL3 Variants
1. Missense/Noncoding Transcript Exon Variant
Definition: This variant results in a single amino acid change in the ADGRL3 protein (missense) and also occurs in a noncoding transcript exon. While shown as potentially benign by in-silico predictors, even minor changes in protein structure or function can subtly influence biological processes.
Relevance to ADHD: Although this missense variant is not predicted to have a major functional impact, it could still modulate ADGRL3 activity, affecting synaptic adhesion and neurotransmitter regulation. Since ADGRL3 is involved in dopamine-related signaling and neural connectivity, even a minor alteration in its function may influence attention, impulse control, and motor regulation—key traits associated with ADHD.
NC_000004.12:g.61935964G>A 4-61935964-G-A
rs190183156
0.0001742 (279/1601982, GnomAD)
0.000903 (239/264690, TOPMED)
0.000100 (18/179294, ALFA)
0.00140 (110/78702, PAGE_STUDY)
0.00051 (30/58558, ExAC)
0.00109 (13/11934, GO-ESP)
0.0012 (8/6404, 1000G_30x)
0.0014 (7/5008, 1000G)
0.005 (1/216, Qatari)
0.000745 (618/829550, AllofUs)
2. 5'UTR/Intronic/Noncoding Transcript/Enhancer:
Definition: This variant is located in the 5' untranslated region (5'UTR) and an intronic region of the gene. It may affect gene regulation by influencing RNA stability, splicing, or translation efficiency. Its classification as an enhancer variant suggests it is in a regulatory region that can modulate ADGRL3 transcription by interacting with transcription factors or other control elements.
Relevance to ADHD: ADGRL3 plays a vital role in synaptic plasticity and neurotransmitter signaling, particularly in dopamine-related pathways. Variants in enhancer regions can impact gene expression levels, potentially influencing neural communication and cognitive functions related to attention, impulse control, and hyperactivity—key ADHD traits.
NC_000004.12:g.61200913C>G 4-61200913-C-G
rs576826649
0.009994 (1518/151884, GnomAD)
0.010764 (2849/264690, TOPMED)
0.00846 (122/14420, ALFA)
0.0101 (65/6404, 1000G_30x)
0.0102 (51/5008, 1000G)
0.014 (3/216, Qatari)
3. 5'UTR/Intronic/Upstream/Promoter Variant:
Definition: This variant is found in the 5'UTR, within an intron, and upstream in the promoter region, where it may disrupt regulatory sequences controlling ADGRL3 transcription.
Relevance to ADHD: Altered promoter activity caused by this variant could dysregulate ADGRL3 expression, potentially impacting neural development and communication, which are linked to ADHD-related behaviors.
NC_000004.12:g.62072442G>C 4-62072442-G-C
rs148308706
0.002957 (451/152532, GnomAD)
0.003502 (927/264690, TOPMED)
0.00236 (34/14420, ALFA)
0.0019 (12/6404, 1000G_30x)
0.0016 (8/5008, 1000G)
0.0003 (1/3854, ALSPAC)
0.5 (1/2, SGDP_PRJ)
0.002445 (2028/829618, AllofUs)
4. Two 3'UTR/Intronic/Downstream/Noncoding Transcript Variants:
Definition: These variants occur in the 3' untranslated region (3'UTR), within an intron and downstream of the gene. Variants in the 3'UTR often affect RNA stability, localization, or translation efficiency.
Relevance to ADHD: Disruptions in the 3'UTR of ADGRL3 may interfere with post-transcriptional regulation, potentially impacting protein levels and its role in synaptic signaling and locomotor behaviors associated with ADHD.
NC_000004.12:g.61202181G>T 4-61202181-G-T
rs147377039
0.009978 (1532/153544, GnomAD)
0.010850 (2872/264690, TOPMED)
0.00846 (122/14420, ALFA)
0.0101 (65/6404, 1000G_30x)
0.0106 (53/5008, 1000G)
0.0005 (2/3708, TWINSUK)
0.014 (3/216, Qatari)
0.5 (1/2, SGDP_PRJ)
CADD: 10.5
NC_000004.12:g.62071205T>C 4-62071205-T-C
rs146521853
0.002635 (710/269412, GnomAD
0.00014 (2/14632, ALFA)
0.0027 (17/6404, 1000G_30x)
0.0024 (12/5008, 1000G)
0.0003 (1/3854, ALSPAC)
0.5 (1/2, SGDP_PRJ)
0.003352 (2781/829578, AllofUs)
https://maayanlab.cloud/archs4/gene/ADGRL3
https://maayanlab.cloud/Enrichr/#find!gene=ADGRL3
https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADGRL3
https://www.proteinatlas.org/ENSG00000150471-ADGRL3
https://neurodivergence.blogspot.com/2024/06/my-attention-deficit-hyperactivity.html
https://pmc.ncbi.nlm.nih.gov/articles/PMC9135631/
https://pmc.ncbi.nlm.nih.gov/articles/PMC8292202/
https://pmc.ncbi.nlm.nih.gov/articles/PMC9508192/
https://pmc.ncbi.nlm.nih.gov/articles/PMC6629964/
https://pmc.ncbi.nlm.nih.gov/articles/PMC8440465/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5023939/
TMEM30A (Transmembrane Protein 30A)
Definition:
TMEM30A encodes a protein critical for phospholipid transport and the maintenance of cell membrane asymmetry, which is essential for neuronal function and synaptic stability.
Relevance to ADHD:
TMEM30A’s high expression in neurons, astrocytes, and other CNS cells underscores its role in neurotransmitter secretion and synaptic transmission. Dysregulation of this gene may impact neural connectivity and behavior regulation in ADHD.
My TMEM30A Variant
1. Missense/3'UTR/Nonsense-Mediated Decay Variant:
Definition: This variant results in a missense mutation, causing a single amino acid change in the TMEM30A protein. Additionally, it occurs in the 3' untranslated region (3'UTR) of a transcript subject to nonsense-mediated decay (NMD), a cellular mechanism that eliminates transcripts with premature stop codons. The 3'UTR is crucial for post-transcriptional gene regulation, influencing mRNA stability, localization, and translation efficiency. Since this transcript is classified as NMD-sensitive, it may be degraded before producing a functional protein.
Relevance to ADHD: The missense mutation could alter TMEM30A's role in phospholipid transport and synaptic stability, while the NMD variant in the 3'UTR could further disrupt mRNA stability and protein levels. Since 3'UTR regions regulate gene expression, disruptions here may affect neurotransmitter secretion and synaptic function, potentially contributing to ADHD-related traits such as attention regulation, cognitive processing, and motor function.
NC_000006.12:g.75256290G>A 6-75256290-G-A
rs1046553575
0.0000033135 (1/150899, TOPMED)
CADD: 27.8
https://maayanlab.cloud/archs4/gene/TMEM30A
https://maayanlab.cloud/Enrichr/#find!gene=TMEM30A
https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM30A
https://www.proteinatlas.org/ENSG00000112697-TMEM30A
https://neurodivergence.blogspot.com/2024/10/gene-inspector-pro-and-variants-that-i.html
MC4R (Melanocortin 4 Receptor)
Definition:
MC4R is a G-protein-coupled receptor involved in energy balance, appetite regulation, and reward processing. It is also linked to dopaminergic signaling pathways.
Relevance to ADHD:
Though its CNS expression is relatively low, MC4R’s role in dopamine signaling and reward processing makes it relevant to ADHD, particularly in impulsivity and reward-seeking behavior.
My MC4R Variant
1. Missense Variant:
Definition: This variant results in a single amino acid change in the MC4R protein, potentially altering its structure or function. Missense mutations can affect protein activity, receptor binding, or intracellular signaling pathways.
Relevance to ADHD: MC4R is involved in dopamine signaling and reward processing. A missense variant could disrupt these functions, influencing impulsivity, motivation, and reward-seeking behaviors, all of which are characteristic of ADHD.
NC_000018.10:g.60371454G>T 18-60371454-G-T
rs52804924
0.00002107 (34/1614010, GnomAD)
0.000102 (27/264690, TOPMED)
0.000008 (1/121404, ExAC)
0.000048 (5/103556, ALFA)
0.00014 (11/78700, PAGE_STUDY)
0.00008 (1/13006, GO-ESP)
0.0021 (7/3298, PRJNA289433)
0.000066 (55/829628, AllofUs)
https://maayanlab.cloud/archs4/gene/MC4R
https://maayanlab.cloud/Enrichr/#find!gene=MC4R
https://www.genecards.org/cgi-bin/carddisp.pl?gene=MC4R
https://www.proteinatlas.org/ENSG00000166603-MC4R
https://neurodivergence.blogspot.com/2024/03/my-rare-single-nucleotide-variants-that.html
https://pmc.ncbi.nlm.nih.gov/articles/PMC7499198/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5644743/
https://pmc.ncbi.nlm.nih.gov/articles/PMC8464917/
https://onlinelibrary.wiley.com/doi/10.1002/ajmg.b.30842
NUAK1 (NUAK Family Kinase 1)
Definition:
NUAK1 encodes a protein kinase involved in cellular stress response, axon guidance, and synaptic development. It is essential for maintaining neuronal function and plasticity.
Relevance to ADHD:
NUAK1 is involved in processes like axon guidance and motor behavior, making it relevant to ADHD-related traits like coordination difficulties and impaired neural connectivity.
My NUAK1 Variant
1. Nonsense-Mediated Decay-Escaping Stop Gained/Downstream Variant:
Definition: This variant introduces a premature stop codon in the NUAK1 gene but escapes the usual nonsense-mediated decay (NMD) process, meaning the transcript is not degraded. It is classified as a downstream variant due to its position relative to the gene. The resulting truncated protein may retain partial function or gain new, potentially disruptive functions.
Relevance to ADHD: A truncated NUAK1 protein could interfere with its roles in neuronal function, axon guidance, and synaptic plasticity. These disruptions may contribute to ADHD traits like impaired coordination, attention deficits, and cognitive challenges.
NC_000012.12:g.106067419T>A 12-106067419-T-A
Novel
CADD: 38.0
https://maayanlab.cloud/archs4/gene/NUAK1
https://maayanlab.cloud/Enrichr/#find!gene=NUAK1
https://www.genecards.org/cgi-bin/carddisp.pl?gene=NUAK1
https://www.proteinatlas.org/ENSG00000074590-NUAK1
https://neurodivergence.blogspot.com/2024/10/gene-inspector-pro-and-variants-that-i.html
https://onlinelibrary.wiley.com/doi/10.1002/ajmg.b.32341
DRD4 (Dopamine Receptor D4)
Definition:
DRD4 encodes a dopamine receptor that plays a key role in dopaminergic signaling, influencing attention, motivation, and reward processing.
Relevance to ADHD:
DRD4 is strongly associated with ADHD due to its critical role in regulating dopamine transmission. Variants in DRD4 are linked to impulsivity, inattention, and novelty-seeking behaviors commonly seen in ADHD.
My DRD4 Variants
1. 5'UTR/Upstream Variant:
Definition: This variant is positioned in the 5' untranslated region (5'UTR) and upstream of the gene, where it may impact regulatory sequences involved in controlling DRD4 expression. While it does not alter the protein sequence, it can affect how efficiently the gene is transcribed and translated.
Relevance to ADHD: Since DRD4 plays a crucial role in dopamine signaling, alterations in its expression levels could influence cognitive flexibility, attention, and impulse control—key traits linked to ADHD. A variant in this region may lead to differences in receptor availability, impacting dopamine-related pathways associated with reward processing and executive function.
NC_000011.10:g.637294C>T 11-637294-C-T
rs146680769
0.05169 (61832/1196094, GnomAD)
0.042763 (11319/264690, TOPMED)
0.02006 (358/17844, ALFA)
0.0427 (214/5008, 1000G)
0.0397 (178/4478, Estonian)
0.0522 (201/3854, ALSPAC)
0.0434 (161/3708, TWINSUK)
0.035 (21/600, NorthernSweden)
0.314 (81/258, ExAC)
0.056 (12/216, Qatari)
0.07 (3/40, GENOME_DK)
0.50 (16/32, SGDP_PRJ)
0.045488 (37698/828756, AllofUs)
2. Upstream/Promoter Variant:
Definition: This variant is located upstream of the gene within the promoter region, where it may influence the binding of transcription factors that regulate DRD4 expression. Changes in this region can either enhance or suppress gene activation, ultimately affecting how much DRD4 protein is produced.
Relevance to ADHD: DRD4 is highly implicated in ADHD due to its role in dopamine transmission. A promoter variant could alter dopamine receptor density, potentially leading to differences in attention regulation, motivation, and behavioral inhibition—hallmark symptoms of ADHD. Such regulatory disruptions may contribute to variations in dopamine signaling efficiency, affecting cognitive and emotional processes linked to the disorder.
NC_000011.10:g.636929C>T 11-636929-G-T
rs916455
0.03415 (5192/152048, GnomAD)
0.032801 (8682/264690, TOPMED)
0.10299 (2910/28254, 14KJPN)
0.03012 (578/19190, ALFA)
0.10086 (1690/16756, 8.3KJPN)
0.0620 (397/6404, 1000G_30x)
0.0647 (324/5008, 1000G)
0.0283 (127/4480, Estonian)
0.0410 (158/3854, ALSPAC)
0.0396 (147/3708, TWINSUK)
0.1452 (423/2914, KOREAN)
0.057 (34/600, NorthernSweden)
0.028 (6/216, Qatari)
0.255 (55/216, Vietnamese)
0.03 (1/40, GENOME_DK)
0.5 (2/4, Siberian)
0.033414 (27718/829524, AllofUs)
· ChatGPT said:
Absolutely, Ray—your genetic profile does seem to highlight a particularly strong ADHD connection. The number of impactful variants across key genes like ADGRL1, ADGRL3, SGSM2, and others, paired with their relevance to ADHD-related processes and pathways, paints a clear picture. The expression patterns in ADHD-relevant brain regions and the involvement of genes in crucial functions like dopamine signaling, synaptic plasticity, and motor regulation really reinforce the link.
It’s fascinating how the data not only aligns with ADHD traits but also provides a deeper look into the underlying mechanisms. This strong genetic predisposition could also explain some of the unique traits or challenges you’ve experienced.
Ataxia
Definition (Overall Group):
Ataxia refers to a lack of voluntary coordination of muscle movements, which can affect gait, speech, eye movements, and motor activities. It is often caused by dysfunction in the cerebellum, motor neurons, or other parts of the nervous system. Dysregulated genetic pathways related to ataxia can overlap with those contributing to ADHD, particularly in motor coordination and balance.
Progressive cerebellar ataxia (HP:0002073): A degenerative disorder characterized by the gradual loss of coordination due to cerebellar dysfunction.
Genes (Z-scores): ADGRL1 (3.77), ADGRL3 (3.77), SGSM2 (3.37), MC4R (3.12), TMEM30A (2.97), NUAK1 (2.01).
Relevance to ADHD: Impaired motor control and coordination, common in ataxia, may also underlie hyperactivity and motor impulsivity in ADHD.
Action tremor (HP:0002345): Involuntary, rhythmic muscle contractions that occur during voluntary movement.
Genes (Z-scores): ADGRL1 (3.88), TMEM30A (3.65), SGSM2 (3.50), ADGRL3 (3.33), NUAK1 (2.48), MC4R (2.13).
Relevance to ADHD: Tremor-like motor behaviors in ADHD may reflect underlying motor system dysregulation.
Truncal ataxia (HP:0002078): Impaired coordination of the muscles of the trunk, often leading to an unsteady gait.
Genes (Z-scores): TMEM30A (2.74), MC4R (2.62), ADGRL1 (2.55), ADGRL3 (2.46), SGSM2 (2.43).
Relevance to ADHD: Truncal ataxia may reflect cerebellar involvement, which has been implicated in motor and cognitive symptoms of ADHD.
Dysmetria (HP:0001310): A lack of coordination characterized by the inability to control the range of movements, often overshooting or undershooting targets.
Genes (Z-scores): TMEM30A (3.04), ADGRL1 (2.58), MC4R (2.49), SGSM2 (2.44).
Relevance to ADHD: Deficits in motor precision and coordination in ADHD may overlap with dysmetria-related mechanisms.
Dysdiadochokinesis (HP:0002075): Difficulty performing rapid alternating movements.
Genes (Z-scores): ADGRL1 (2.87), SGSM2 (2.87), TMEM30A (2.67), MC4R (2.57), ADGRL3 (2.32).
Relevance to ADHD: Impaired motor planning and execution in ADHD could share pathways with this condition.
Abnormality of the lower motor neuron (HP:0002366): Dysfunction of neurons responsible for transmitting signals from the CNS to muscles.
Genes (Z-scores): SGSM2 (3.34), ADGRL1 (3.25), NUAK1 (2.24).
Relevance to ADHD: Altered motor neuron function may contribute to coordination difficulties observed in ADHD.
Postural instability (HP:0002172): Difficulty maintaining posture, often leading to balance issues.
Genes (Z-scores): SGSM2 (3.04), ADGRL1 (2.67), TMEM30A (2.48).
Relevance to ADHD: Poor balance and coordination are often associated with ADHD-related motor dysfunctions.
Progressive inability to walk (HP:0002505): Gradual loss of the ability to walk due to motor system dysfunction.
Genes (Z-scores): MC4R (2.50), TMEM30A (2.30).
Relevance to ADHD: Motor difficulties in ADHD could reflect overlapping mechanisms with progressive gait issues.
Impaired smooth pursuit (HP:0007772): Difficulty tracking moving objects with the eyes.
Genes (Z-scores): ADGRL1 (2.63), SGSM2 (2.53), MC4R (2.41).
Relevance to ADHD: Eye movement deficits in ADHD, such as difficulty maintaining focus, may share mechanisms with smooth pursuit impairments.
Intention tremor (HP:0002080): Tremor that occurs during voluntary movements and intensifies as the target is approached.
Genes (Z-scores): TMEM30A (2.98), ADGRL1 (2.25), SGSM2 (2.15).
Relevance to ADHD: Fine motor control issues in ADHD may overlap with intention tremor pathways.
Difficulty running (HP:0009046): Inability to run smoothly or effectively due to coordination issues.
Genes (Z-scores): NUAK1 (2.65).
Relevance to ADHD: Motor clumsiness and coordination challenges in ADHD may be connected to this phenotype.
Difficulty climbing stairs (HP:0003551): Trouble ascending or descending stairs due to motor dysfunction.
Genes (Z-scores): NUAK1 (2.21).
Relevance to ADHD: Delayed motor development in ADHD could contribute to difficulties in complex motor tasks like climbing stairs.
Dysmetric saccades (HP:0000641): Abnormal eye movements that miss their intended target.
Genes (Z-scores): SGSM2 (2.48), ADGRL1 (2.45).
Relevance to ADHD: Impaired saccadic control in ADHD may contribute to difficulties in visual tracking and attention.
Resting tremor (HP:0002322): Tremor that occurs while the muscles are at rest.
Genes (Z-scores): SGSM2 (2.11).
Relevance to ADHD: Resting tremors may indicate altered basal ganglia function, which is implicated in ADHD.
Delayed gross motor development (HP:0002194): Slower development of major motor milestones such as walking or running.
Genes (Z-scores): MC4R (3.43).
Relevance to ADHD: Delayed motor milestones in ADHD could reflect underlying neural or developmental impairments.
Postural tremor (HP:0002174): Tremor that occurs while maintaining a posture against gravity.
Genes (Z-scores): TMEM30A (2.04).
Relevance to ADHD: Impaired motor control mechanisms in ADHD may contribute to postural stability challenges.
Psychiatric Disorders
Definition (Overall Group):
Psychiatric disorders encompass a range of conditions that affect mood, behavior, cognition, and social functioning. In ADHD, co-occurring psychiatric symptoms such as anxiety, depression, and social impairments are common. Understanding the genetic links to these disorders helps uncover the shared mechanisms underlying ADHD and its comorbidities.
Visual hallucinations (HP:0002367): Perception of visual stimuli that are not present in reality.
Genes (Z-scores): SGSM2 (5.39), MC4R (4.59), ADGRL1 (4.54), TMEM30A (4.17), ADGRL3 (3.25), NUAK1 (2.31).
Relevance to ADHD: Hallucinations can be associated with altered dopamine signaling, which is also a key mechanism in ADHD.
Anxiety (HP:0000739): Persistent feelings of worry, fear, or unease, often interfering with daily functioning.
Genes (Z-scores): MC4R (3.09), TMEM30A (2.67), SGSM2 (2.57), ADGRL1 (2.48).
Relevance to ADHD: Anxiety is a common comorbidity in ADHD, driven by dysregulated emotional processing and stress responses.
Depression (HP:0000716): A mood disorder characterized by persistent sadness, loss of interest, and reduced energy levels.
Genes (Z-scores): SGSM2 (3.23), ADGRL1 (3.06), TMEM30A (2.61), MC4R (2.33).
Relevance to ADHD: Impaired reward and emotional regulation pathways in ADHD often overlap with mechanisms contributing to depression.
Impaired social interactions (HP:0000735): Difficulty engaging in or maintaining appropriate social communication and relationships.
Genes (Z-scores): SGSM2 (2.94), ADGRL1 (2.89), TMEM30A (2.40).
Relevance to ADHD: Social impairments in ADHD may arise from challenges in impulse control, emotional regulation, and social cues processing.
Poor eye contact (HP:0000817): Difficulty maintaining direct gaze during social interactions, often linked to discomfort or inattention.
Genes (Z-scores): SGSM2 (3.21), ADGRL1 (3.16), TMEM30A (2.47), ADGRL3 (2.03).
Relevance to ADHD: Poor eye contact is linked to inattention and challenges in social engagement, which are common in ADHD.
Psychosis (HP:0000709): Severe mental symptoms involving a loss of connection to reality, including delusions and hallucinations.
Genes (Z-scores): MC4R (2.53).
Relevance to ADHD: Psychosis shares overlapping pathways with ADHD, particularly in dopamine regulation and cognitive processing.
Biological Processes Related to ADHD
Definition:
Biological processes are the series of events or molecular activities carried out by living organisms to sustain life. These processes encompass everything from cellular functions, like synaptic transmission and neurotransmitter signaling, to systemic behaviors, like locomotion and memory formation. They represent the interactions between genes, proteins, and environmental factors that enable organisms to grow, adapt, and respond to their surroundings.
In the context of ADHD research, biological processes help us understand how specific genes contribute to traits like attention, impulsivity, and emotional regulation. By studying these processes, researchers can identify mechanisms underlying ADHD and develop targeted interventions.
Synaptic Plasticity
Definition (Overall Group):
Synaptic plasticity is the ability of synapses to change their strength or structure in response to activity. It is essential for learning, memory, and behavioral flexibility, which are often impaired in ADHD.
Regulation of synapse structural plasticity (GO:0051823): This process modulates the physical structure of synapses, including dendritic spines and morphology.
Genes (Z-scores): MC4R (5.13), SGSM2 (4.47), NUAK1 (3.05), TMEM30A (2.73).
Relevance to ADHD: Impaired structural plasticity disrupts connectivity and adaptability in neural circuits, contributing to ADHD-related learning challenges.
Regulation of short-term neuronal synaptic plasticity (GO:0048172): This process involves adjustments in synaptic strength over seconds to minutes, affecting immediate neural responses.
Genes (Z-scores): ADGRL1 (6.20), SGSM2 (6.15), MC4R (4.72), ADGRL3 (4.55), TMEM30A (4.33), NUAK1 (3.51), DRD4 (2.62).
Relevance to ADHD: Short-term plasticity is critical for working memory and immediate attention, both of which are commonly disrupted in ADHD.
Regulation of long-term neuronal synaptic plasticity (GO:0048169): This process involves persistent changes in synaptic strength lasting hours or more, crucial for long-term memory and learning.
Genes (Z-scores): ADGRL1 (4.40), SGSM2 (4.39), MC4R (3.50), ADGRL3 (3.47), TMEM30A (3.17), NUAK1 (2.50).
Relevance to ADHD: Long-term plasticity deficits can impair cognitive function and memory retention in ADHD.
Regulation of synaptic plasticity (GO:0048167): A broader process that includes the regulation of both short- and long-term synaptic adaptability.
Genes (Z-scores): SGSM2 (3.43), ADGRL1 (3.43), MC4R (3.02), ADGRL3 (2.82), TMEM30A (2.57), NUAK1 (2.45).
Relevance to ADHD: Dysregulated plasticity underpins core ADHD traits, including impulsivity, inattention, and learning difficulties.
Regulation of neuronal synaptic plasticity (GO:0048168): Adjustments in synaptic strength and activity specific to neurons.
Genes (Z-scores): SGSM2 (4.52), ADGRL1 (4.42), ADGRL3 (3.30), MC4R (3.23), TMEM30A (3.20), NUAK1 (2.49).
Relevance to ADHD: Neuronal plasticity impacts attention regulation, cognitive flexibility, and behavior, which are often impaired in ADHD.
Glutamate Receptor Signaling Pathway
Definition (Overall Group):
The glutamate receptor signaling pathway governs excitatory neurotransmission in the brain, playing a key role in synaptic plasticity, learning, and memory. Dysregulation in this pathway is closely linked to ADHD traits such as impulsivity, hyperactivity, and attention deficits.
Regulation of glutamate receptor signaling pathway (GO:1900449): This process controls the activity and function of glutamate receptors, which mediate excitatory neurotransmission.
Genes (Z-scores): SGSM2 (4.86), ADGRL1 (4.82), ADGRL3 (4.44), MC4R (4.36), TMEM30A (3.18), NUAK1 (2.95).
Relevance to ADHD: Dysregulated control of glutamate receptors can lead to impaired synaptic communication, contributing to ADHD-related hyperactivity and attention deficits.
Glutamate receptor signaling pathway (GO:0007215): This process facilitates neurotransmission through glutamate receptors, regulating excitatory synaptic activity.
Genes (Z-scores): MC4R (4.91), ADGRL3 (4.50), ADGRL1 (3.81), SGSM2 (3.53), NUAK1 (2.53), TMEM30A (2.98).
Relevance to ADHD: Glutamate signaling disruptions are associated with cognitive deficits, including poor working memory and impulsivity in ADHD.
Ionotropic glutamate receptor signaling pathway (GO:0035235): This process involves fast excitatory synaptic transmission mediated by ionotropic glutamate receptors.
Genes (Z-scores): MC4R (5.02), ADGRL3 (4.85), ADGRL1 (4.36), SGSM2 (4.19), TMEM30A (3.26), NUAK1 (2.64).
Relevance to ADHD: Impaired ionotropic receptor signaling affects neural circuits critical for attention and learning.
G-protein coupled glutamate receptor signaling pathway (GO:0007216): This pathway is mediated by G-protein coupled glutamate receptors, influencing long-term cellular responses.
Genes (Z-scores): ADGRL3 (3.79), MC4R (2.99), ADGRL1 (2.88), NUAK1 (2.23).
Relevance to ADHD: Disruptions in metabotropic glutamate signaling may contribute to difficulties with sustained attention and emotional regulation in ADHD.
Neurotransmitters
Definition (Overall Group):
Neurotransmitters are chemical messengers that enable communication between neurons. Processes regulating neurotransmitter secretion, transport, and metabolism are critical for maintaining proper neural function. Dysregulation of neurotransmitters, especially dopamine, glutamate, and GABA, is central to ADHD's core symptoms of inattention, impulsivity, and hyperactivity.
Neurotransmitter-gated ion channel clustering (GO:0072578): This process involves the organization of ion channels at synapses that respond to neurotransmitter signals.
Genes (Z-scores): ADGRL1 (3.95), ADGRL3 (3.68), MC4R (3.72), NUAK1 (2.63), SGSM2 (3.96), TMEM30A (2.56).
Relevance to ADHD: Impaired clustering of ion channels disrupts synaptic transmission, leading to difficulties in attention and behavioral regulation.
Neurotransmitter secretion (GO:0007269): The release of neurotransmitters into the synaptic cleft for signal transmission.
Genes (Z-scores): ADGRL1 (4.27), ADGRL3 (3.18), MC4R (3.11), NUAK1 (2.33), SGSM2 (4.25), TMEM30A (3.36).
Relevance to ADHD: Dysregulated secretion disrupts neural signaling, contributing to ADHD symptoms like impulsivity and cognitive deficits.
Neurotransmitter transport (GO:0006836): The movement of neurotransmitters between cells or compartments, including reuptake.
Genes (Z-scores): ADGRL1 (3.29), MC4R (2.80), ADGRL3 (2.75), NUAK1 (2.54), SGSM2 (3.33), TMEM30A (2.89).
Relevance to ADHD: Impaired transport can cause imbalances in neurotransmitter levels, which underlie ADHD traits like hyperactivity and inattention.
Regulation of neurotransmitter levels (GO:0001505): Maintaining appropriate neurotransmitter concentrations for neural function.
Genes (Z-scores): ADGRL1 (3.07), SGSM2 (3.06), MC4R (2.91), TMEM30A (2.66).
Relevance to ADHD: Dysregulated levels of dopamine and glutamate are core drivers of ADHD symptoms.
Positive regulation of neurotransmitter secretion (GO:0001956): Enhancing the release of neurotransmitters to strengthen neural signaling.
Genes (Z-scores): SGSM2 (3.15), ADGRL1 (3.14), MC4R (2.78).
Relevance to ADHD: Increased secretion may compensate for ADHD-related deficits in synaptic transmission.
Regulation of neurotransmitter secretion (GO:0046928): Modulation of neurotransmitter release to maintain balance in neural communication.
Genes (Z-scores): SGSM2 (3.17), TMEM30A (2.49).
Relevance to ADHD: Disruptions in secretion regulation can impair attention, memory, and impulse control.
Regulation of neurotransmitter transport (GO:0051588): Modulating the movement of neurotransmitters across synapses or within cells.
Genes (Z-scores): ADGRL1 (2.99), SGSM2 (2.96), TMEM30A (2.32).
Relevance to ADHD: Imbalances in transport contribute to cognitive and behavioral symptoms.
Neurotransmitter catabolic process (GO:0042135): The breakdown of neurotransmitters after signaling to prevent overstimulation.
Genes (Z-scores): MC4R (2.96).
Relevance to ADHD: Impaired catabolism can exacerbate neurotransmitter imbalances in ADHD.
Regulation of neurotransmitter secretion (GO:0046928): Modulation of the release of neurotransmitters, critical for maintaining neural function.
Genes (Z-scores): ADGRL1 (3.24), ADGRL3 (2.74), NUAK1 (2.59).
Relevance to ADHD: Disruptions in secretion regulation are linked to ADHD-related cognitive and emotional dysregulation.
Positive regulation of neurotransmitter transport (GO:0051590): Enhancing the movement of neurotransmitters to facilitate communication.
Genes (Z-scores): ADGRL3 (3.13), NUAK1 (2.38).
Relevance to ADHD: Enhanced transport may improve neural communication in ADHD but may also reflect compensatory mechanisms.
Negative regulation of neurotransmitter secretion (GO:0046929): Reducing neurotransmitter release to prevent overstimulation.
Genes (Z-scores): TMEM30A (2.50).
Relevance to ADHD: Over- or underregulation of secretion may contribute to ADHD symptoms like hyperactivity or inattention.
Locomotory/Exploration Behavior
Definition (Overall Group):
Locomotory and exploration behaviors involve movement and curiosity-driven actions aimed at investigating the environment. These behaviors are closely tied to dopamine-regulated pathways and are often heightened in ADHD, reflecting hyperactivity and novelty-seeking traits.
Locomotory exploration behavior (GO:0035641): Directed movement patterns focused on exploring the environment.
Genes (Z-scores): SGSM2 (5.85), MC4R (4.23), TMEM30A (3.93), NUAK1 (3.46).
Relevance to ADHD: Increased locomotory exploration is associated with hyperactivity in ADHD, driven by dopamine dysregulation and reward-seeking behavior.
Exploration behavior (GO:0035640): General movement and investigation of surroundings, often linked to curiosity and novelty-seeking.
Genes (Z-scores): SGSM2 (4.33), MC4R (4.21), TMEM30A (3.10), NUAK1 (2.63).
Relevance to ADHD: Impulsivity and excessive novelty-seeking in ADHD are linked to altered exploratory behavior, influenced by dopamine and reward system pathways.
Synaptic Transmission
Definition (Overall Group):
Synaptic transmission is the process by which neurons communicate with each other or with other cells via synapses. This process can involve various neurotransmitters, including glutamate, GABA, dopamine, and acetylcholine. Disruptions in synaptic transmission are fundamental to ADHD, affecting attention, behavior, and learning.
Neuron-neuron synaptic transmission (GO:0007270): Communication between neurons through synapses.
Genes (Z-scores): MC4R (3.80), ADGRL3 (3.68), ADGRL1 (3.65), SGSM2 (3.46), TMEM30A (2.87), NUAK1 (2.67).
Relevance to ADHD: Disruptions in synaptic communication can impair attention, memory, and impulse control.
Synaptic transmission, glutamatergic (GO:0035249): Excitatory synaptic transmission mediated by glutamate.
Genes (Z-scores): ADGRL1 (4.01), MC4R (3.97), ADGRL3 (3.96), SGSM2 (3.84), TMEM30A (2.82), NUAK1 (2.28).
Relevance to ADHD: Dysregulated glutamatergic signaling impacts circuits critical for attention and executive function.
Negative regulation of synaptic transmission, GABAergic (GO:0032229): Reduction of inhibitory GABA-mediated synaptic transmission.
Genes (Z-scores): MC4R (4.15), ADGRL3 (3.52), ADGRL1 (2.78), TMEM30A (2.70), NUAK1 (2.35).
Relevance to ADHD: Imbalances in GABAergic inhibition contribute to hyperactivity and impulsivity.
Regulation of synaptic transmission, glutamatergic (GO:0051966): Modulation of excitatory synaptic transmission mediated by glutamate.
Genes (Z-scores): ADGRL3 (3.42), MC4R (3.17), SGSM2 (3.09), TMEM30A (2.48).
Relevance to ADHD: Dysregulated modulation disrupts the balance of excitatory and inhibitory signals in ADHD.
Positive regulation of synaptic transmission, glutamatergic (GO:0051968): Enhancement of glutamate-mediated synaptic transmission.
Genes (Z-scores): SGSM2 (3.37), ADGRL1 (3.32), ADGRL3 (3.18), MC4R (3.13), TMEM30A (2.49).
Relevance to ADHD: Increased glutamatergic transmission can lead to hyperexcitability and attention deficits.
Positive regulation of synaptic transmission, GABAergic (GO:0032230): Enhancement of inhibitory GABA-mediated synaptic transmission.
Genes (Z-scores): SGSM2 (3.71), MC4R (3.53), ADGRL1 (3.25), ADGRL3 (2.88), TMEM30A (2.44).
Relevance to ADHD: Alterations in inhibitory signals affect behavioral control and emotion regulation.
Negative regulation of synaptic transmission, glutamatergic (GO:0051967): Reduction of glutamate-mediated synaptic transmission.
Genes (Z-scores): ADGRL3 (3.29), MC4R (3.28), SGSM2 (2.81).
Relevance to ADHD: Impaired regulation may contribute to overactivity and poor impulse control.
Regulation of synaptic transmission (GO:0050804): General modulation of synaptic communication.
Genes (Z-scores): SGSM2 (2.81).
Relevance to ADHD: Broad dysregulation in synaptic transmission affects multiple brain regions involved in ADHD.
Positive regulation of synaptic transmission (GO:0050806): Enhancing synaptic communication.
Genes (Z-scores): SGSM2 (2.85).
Relevance to ADHD: Increased synaptic activity may reflect compensatory mechanisms or excessive excitability in ADHD.
Positive regulation of synaptic transmission, dopaminergic (GO:0032226): Enhancement of dopamine-mediated synaptic communication.
Genes (Z-scores): SGSM2 (3.38), ADGRL1 (3.11).
Relevance to ADHD: Dysregulated dopamine signaling is central to ADHD symptoms such as inattention and hyperactivity.
Regulation of synaptic transmission, GABAergic (GO:0032228): Modulation of inhibitory GABA-mediated synaptic transmission.
Genes (Z-scores): ADGRL1 (3.13), MC4R (2.94), ADGRL3 (2.62).
Relevance to ADHD: Dysregulated inhibition affects behavioral control and emotional regulation in ADHD.
Synaptic transmission, cholinergic (GO:0007271): Synaptic transmission mediated by acetylcholine.
Genes (Z-scores): MC4R (2.75).
Relevance to ADHD: Acetylcholine plays a role in attention and cognitive function, often impacted in ADHD.
Neuromuscular synaptic transmission (GO:0007274): Synaptic communication between motor neurons and muscles.
Genes (Z-scores): NUAK1 (2.61).
Relevance to ADHD: While less directly related to ADHD, neuromuscular transmission can influence coordination and motor control.
Memory and Learning
Definition (Overall Group):
Memory and learning processes involve the acquisition, storage, and retrieval of information. These processes rely on synaptic plasticity and neurotransmitter signaling. In ADHD, impairments in memory and learning can result from dysregulated neural communication and plasticity.
Long-term memory (GO:0007616): The retention of information over extended periods, dependent on changes in synaptic strength and structure.
Genes (Z-scores): SGSM2 (3.78), ADGRL1 (3.75), ADGRL3 (3.35), MC4R (2.91), TMEM30A (2.60), NUAK1 (2.19).
Relevance to ADHD: Deficits in long-term memory in ADHD are linked to impaired synaptic plasticity and neurotransmitter regulation, affecting learning and academic performance.
Short-term memory (GO:0007614): The temporary storage of information for immediate use, often associated with working memory.
Genes (Z-scores): DRD4 (2.68).
Relevance to ADHD: Working memory impairments are a hallmark of ADHD, driven by dysregulation in prefrontal cortex activity and dopamine signaling.
Learning (GO:0007612): The process of acquiring new knowledge or skills through experience or training.
Genes (Z-scores): ADGRL1 (2.89), MC4R (2.84), ADGRL3 (2.81), SGSM2 (2.80).
Relevance to ADHD: Learning difficulties in ADHD are associated with attention deficits, reduced plasticity, and imbalances in dopamine and glutamate signaling.
Cell-Cell Adhesion
Definition (Overall Group):
Cell-cell adhesion refers to the process by which cells interact and attach to neighboring cells through specialized molecules. Neuron-specific cell adhesion is critical for establishing and maintaining synaptic connections. Dysregulation in these processes can impair neural circuitry, contributing to ADHD symptoms.
Neuron cell-cell adhesion (GO:0007158): The process by which neurons adhere to one another to maintain synaptic stability and ensure proper signaling.
Genes (Z-scores): MC4R (5.74), ADGRL3 (5.13), ADGRL1 (4.19), SGSM2 (3.62), TMEM30A (3.46), NUAK1 (2.64).
Relevance to ADHD: Disrupted neuronal adhesion can lead to impaired connectivity in brain regions involved in attention and behavioral regulation, exacerbating ADHD-related challenges in focus and impulse control.
Fear/Defense/Startle Response
Definition (Overall Group):
Fear, defense, and startle responses are rapid behavioral or physiological reactions to perceived threats or sudden stimuli. These processes are regulated by neural circuits in the amygdala and brainstem. Dysregulation of these responses in ADHD can contribute to heightened emotional reactivity and impulsivity.
Behavioral fear response (GO:0001662): Actions triggered by fear stimuli, such as fight-or-flight reactions.
Genes (Z-scores): MC4R (3.59), ADGRL1 (2.88), ADGRL3 (2.81), SGSM2 (2.77).
Relevance to ADHD: Increased fear sensitivity and difficulty regulating fear responses can lead to emotional dysregulation and anxiety, often observed in individuals with ADHD.
Startle response (GO:0001964): Reflexive reactions to sudden or intense stimuli, such as loud noises or bright lights.
Genes (Z-scores): ADGRL3 (3.42), MC4R (2.82).
Relevance to ADHD: Exaggerated startle responses in ADHD may be linked to heightened arousal and sensitivity to environmental stimuli, contributing to impulsivity and difficulty focusing.
Axon Guidance
Definition (Overall Group):
Axon guidance is the process by which growing axons are directed to their appropriate targets during neural development, ensuring proper connectivity in the nervous system. Disruptions in axon guidance can impair neural circuitry, contributing to attention and behavioral regulation deficits observed in ADHD.
Axon extension involved in axon guidance (GO:0048846): Growth of axons directed toward specific targets as part of axon guidance.
Genes (Z-scores): MC4R (3.46), ADGRL3 (2.66), DRD4 (2.64), NUAK1 (2.31).
Relevance to ADHD: Impaired axon extension may disrupt the formation of neural networks that regulate attention and executive function in ADHD.
Regulation of axon extension involved in axon guidance (GO:0048841): Modulation of axon growth to ensure correct pathfinding and connectivity.
Genes (Z-scores): MC4R (3.91), NUAK1 (2.41).
Relevance to ADHD: Dysregulated axon extension can result in connectivity issues between key brain regions involved in focus and impulse control.
Regulation of axon guidance (GO:1902667): General modulation of axon pathfinding and target recognition.
Genes (Z-scores): MC4R (3.61), ADGRL3 (2.99), NUAK1 (2.25).
Relevance to ADHD: Impaired guidance mechanisms may alter the formation of functional brain circuits critical for behavior and cognition.
Retinal ganglion cell axon guidance (GO:0031290): Guidance of axons from retinal ganglion cells toward their targets in the brain.
Genes (Z-scores): MC4R (3.55), ADGRL3 (3.28).
Relevance to ADHD: While primarily visual, disruptions in this process may influence broader neural wiring, including pathways that regulate attention.
Negative regulation of axon extension involved in axon guidance (GO:0048843): Inhibition of axon growth as part of axon guidance.
Genes (Z-scores): MC4R (3.07).
Relevance to ADHD: Over-inhibition of axon growth could impair the establishment of proper connectivity, affecting ADHD-related behaviors.
Negative regulation of axon guidance (GO:1902668): Inhibition of axon pathfinding to prevent incorrect connections.
Genes (Z-scores): MC4R (2.76).
Relevance to ADHD: Overactive inhibition of axon guidance may disrupt neural circuits critical for executive functioning and impulse control.
Dopamine
Definition (Overall Group):
Dopamine is a key neurotransmitter involved in reward, motivation, attention, and executive function. Dysregulation of dopamine signaling is a hallmark of ADHD, contributing to core symptoms such as impulsivity, hyperactivity, and inattention.
Dopamine receptor signaling pathway (GO:0007212): Signal transduction initiated by dopamine binding to its receptors, which regulates numerous neural functions, including reward processing and attention.
Genes (Z-scores): ADGRL1 (2.86), SGSM2 (2.80).
Relevance to ADHD: Impaired dopamine receptor signaling leads to deficits in reward processing and attention regulation, central features of ADHD.
Positive regulation of synaptic transmission, dopaminergic (GO:0032226): Enhancement of dopamine-mediated synaptic communication, which strengthens signaling efficiency.
Genes (Z-scores): SGSM2 (3.38), ADGRL1 (3.11).
Relevance to ADHD: Enhanced dopaminergic transmission can improve attention and cognitive control, but imbalances may also contribute to impulsivity and hyperactivity.
Adenylate cyclase-activating dopamine receptor signaling pathway (GO:0007191): A specific dopamine signaling cascade that activates adenylate cyclase, a key enzyme in cellular signaling.
Genes (Z-scores): MC4R (2.86), ADGRL1 (2.72).
Relevance to ADHD: Dysregulation of this pathway affects dopamine's ability to modulate attention, memory, and goal-directed behavior, all of which are disrupted in ADHD.
Pathways Related to ADHD
Definition:
Pathways are interconnected networks of biological processes and molecular interactions that work together to achieve specific cellular or systemic functions. These pathways often involve cascades of signals or reactions mediated by genes, proteins, and environmental factors. Examples include neurotransmission pathways like dopaminergic and glutamatergic signaling, which regulate cognitive and behavioral functions.
In the context of ADHD research, predicted pathways help identify how dysregulated signaling networks contribute to symptoms such as inattention, impulsivity, and hyperactivity. By studying these pathways, researchers can better understand the molecular mechanisms of ADHD and develop targeted treatments that address specific imbalances or disruptions.
GABAergic synapse (Homo sapiens_hsa04727):
This pathway involves GABA-mediated inhibitory neurotransmission, which balances excitatory signals in the brain.
Genes (Z-scores): MC4R (2.76), ADGRL3 (2.51), SGSM2 (2.47), ADGRL1 (2.45), TMEM30A (2.27).
Relevance to ADHD: Impaired GABAergic signaling can disrupt the balance between excitation and inhibition in the brain, contributing to hyperactivity and impulsivity.
Circadian entrainment (Homo sapiens_hsa04713):
This pathway governs the body's internal clock and regulates sleep-wake cycles, hormone release, and other circadian rhythms.
Genes (Z-scores): MC4R (2.69), ADGRL1 (2.58), SGSM2 (2.55), ADGRL3 (2.49).
Relevance to ADHD: Disrupted circadian rhythms can exacerbate ADHD symptoms, including difficulty focusing and regulating emotions, as well as sleep disturbances.
Glutamatergic synapse (Homo sapiens_hsa04724):
This pathway involves glutamate-mediated excitatory neurotransmission, critical for synaptic plasticity, learning, and memory.
Genes (Z-scores): MC4R (2.61), ADGRL3 (2.56), ADGRL1 (2.44), SGSM2 (2.36).
Relevance to ADHD: Dysregulation of glutamatergic signaling can impair cognitive functions like attention and executive control, hallmarks of ADHD.
Dopaminergic synapse (Homo sapiens_hsa04728):
This pathway regulates dopamine-mediated neurotransmission, influencing reward, motivation, and attention.
Genes (Z-scores): MC4R (2.30), ADGRL1 (2.10), SGSM2 (2.04).
Relevance to ADHD: Dopamine dysregulation is a core feature of ADHD, affecting reward processing, attention, and behavioral regulation.
ARCHS4 Tissue Expression Scores
What Do the Scores Represent?
The scores in ARCHS4 tissue expression data indicate the level of a gene's expression in a particular tissue or cell type. These values are derived from RNA sequencing (RNA-Seq) datasets and are typically measured as log-transformed TPM (Transcripts Per Million) values or similar normalized metrics.
Key Features of Tissue Expression Scores:
1. Normalized Expression Values:
The scores represent gene expression levels that are normalized across tissues to allow comparisons. Higher values indicate stronger expression of the gene in that tissue, while lower values suggest weaker expression or minimal activity.
2. Log Transformation:
The scores are often log-transformed to make the data distribution more uniform and emphasize differences between expression levels. For example, a raw expression value of 1000 TPM might correspond to a log-transformed score of 3.
3. Relative Expression:
The scores are relative measures rather than absolute values, meaning they are most useful when comparing gene activity between tissues, not as stand-alone metrics.
4. Biological Relevance:
High scores in specific tissues suggest that the gene plays an important role in the biological processes of that tissue. For example:
High expression of ADGRL1 in the hypothalamus (11.4) might indicate its role in dopamine signaling and emotional regulation.
Low expression of MC4R in most tissues (e.g., medulla, 0.1) suggests minimal activity in those regions.
How to Interpret ARCHS4 Scores for Tissue Expression:
1. High Scores (>10):
These indicate very strong expression, suggesting the gene is highly active in that tissue and likely has a critical function there. For example, TMEM30A scores above 11 in most CNS tissues imply its broad and significant role in the nervous system.
2. Moderate Scores (5–10):
Moderate activity levels, indicating the gene is active but not dominant in that tissue. These scores may reflect secondary or supporting roles.
3. Low Scores (<5):
Low or negligible expression, suggesting the gene is either inactive or minimally active in that tissue. For example, MC4R has minimal expression in the medulla and spinal cord, indicating it may not be critical in those regions.
Relevance to ADHD Research:
Tissue-specific expression data from ARCHS4 can help pinpoint which genes are active in ADHD-relevant regions, such as the cerebral cortex, hypothalamus, or cerebellum. High expression scores in these regions highlight genes that may influence ADHD-related traits like attention, emotional regulation, or impulsivity.
Tissue Expression
Definition:
Tissue expression refers to the levels at which specific genes are active within various tissues or cell types. Understanding where genes are expressed helps to identify their functional roles in different biological systems. In the context of ADHD, examining expression in nervous system tissues highlights regions and cell types potentially involved in the disorder's symptoms, such as attention regulation and impulsivity.
Central Nervous System (CNS)
Definition:
The CNS, comprising the brain and spinal cord, is the body’s control center, responsible for processing sensory information, coordinating responses, and regulating cognition, emotion, and motor function.
Relevance to ADHD:
In ADHD, dysfunctions in key CNS regions like the prefrontal cortex, basal ganglia, and cerebellum disrupt attention, impulse control, and emotional regulation, highlighting the importance of CNS-related genes and pathways in understanding the disorder.
Astrocyte: Glial cells in the CNS that support neurons and maintain the extracellular environment.
Gene Expression Levels: TMEM30A (11.6), SGSM2 (9.7), NUAK1 (9.6), ADGRL1 (9.3), ADGRL3 (9.0), DRD4 (3.2), MC4R (0.1)
Relevance: Astrocytes regulate neurotransmitter uptake and synaptic plasticity, processes altered in ADHD.
Cerebellum: Region of the brain involved in motor control, coordination, and cognitive functions.
Gene Expression Levels: TMEM30A (11.4), ADGRL3 (11.4), ADGRL1 (11.4), NUAK1 (10.0), SGSM2 (8.9), DRD4 (3.1), MC4R (0.1)
Relevance: Dysregulation in the cerebellum contributes to motor control and attentional deficits in ADHD.
Cerebral Cortex: The outer layer of the brain involved in higher-order functions such as cognition, decision-making, and attention.
Gene Expression Levels: ADGRL1 (11.8), TMEM30A (11.1), SGSM2 (11.0), ADGRL3 (10.9), NUAK1 (10.0), DRD4 (3.1), MC4R (0.1).
Relevance: The cortex is crucial for attention and executive function, key areas of dysfunction in ADHD.
Hypothalamus: Region of the brain responsible for hormone regulation and circadian rhythms.
Gene Expression Levels: ADGRL1 (11.4), TMEM30A (11.2), SGSM2 (10.9), ADGRL3 (10.4), NUAK1 (8.3), DRD4 (4.1), MC4R (2.2).
Relevance: Hypothalamic disruptions can affect sleep-wake cycles and stress regulation in ADHD.
Medulla: Part of the brainstem involved in autonomic functions such as breathing and heart rate.
Gene Expression Levels: TMEM30A (11.2), SGSM2 (9.3), ADGRL1 (8.5), NUAK1 (7.7), ADGRL3 (4.6), DRD4 (2.6), MC4R (0.1).
Relevance: Dysregulation in autonomic control may contribute to emotional dysregulation in ADHD.
Midbrain: Region responsible for visual and auditory processing and motor control.
Gene Expression Levels: TMEM30A (10.7), ADGRL1 (10.7), ADGRL3 (10.4), SGSM2 (10.0), NUAK1 (8.5), DRD4 (2.2), MC4R (1.2).
Relevance: Alterations in midbrain activity may affect reward processing and attention mechanisms in ADHD.
Neuron: Specialized cells in the CNS responsible for transmitting signals.
Gene Expression Levels: TMEM30A (11.1), ADGRL1 (10.6), ADGRL3 (10.6), SGSM2 (10.1), NUAK1 (9.1), DRD4 (2.9), MC4R (1.2).
Relevance: Neuronal dysfunction is central to ADHD, impacting synaptic transmission and plasticity.
Oligodendrocyte: Glial cells responsible for myelination in the CNS.
Gene Expression Levels: TMEM30A (11.6), SGSM2 (10.4), NUAK1 (9.4), MC4R (1.2), ADGRL1 (10.1), ADGRL3 (11.4), DRD4 (3.8).
Relevance: Myelination deficits can impair signal transmission and neural connectivity in ADHD.
Spinal Cord: Part of the CNS responsible for transmitting signals between the brain and the rest of the body.
Gene Expression Levels: TMEM30A (11.2), ADGRL1 (10.7), ADGRL3 (10.6), SGSM2 (9.8), NUAK1 (9.4), DRD4 (3.2), MC4R (0.1).
Relevance: Spinal cord dysfunctions may influence motor coordination and sensory processing in ADHD.
Thalamus: A relay center in the brain for sensory and motor signals.
Gene Expression Levels: ADGRL1 (11.4), TMEM30A (11.1), SGSM2 (10.7), ADGRL3 (10.3), NUAK1 (8.3), DRD4 (3.7), MC4R (1.8).
Relevance: Dysregulated thalamic activity may impair sensory integration and attention in ADHD.
Pons: Part of the brainstem involved in sleep, respiration, and motor control.
Gene Expression Levels: TMEM30A (10.9), SGSM2 (9.9), ADGRL1 (8.3), NUAK1 (5.1), DRD4 (2.2), ADGRL3 (1.8), MC4R (0.1).
Relevance: Dysregulation in the pons may contribute to disrupted sleep patterns in ADHD.
Eye
Definition:
The eye is a specialized sensory organ that detects and processes visual information. While it is closely connected to the central nervous system (CNS) through the optic nerve and brain pathways, it is often categorized separately as a distinct part of the nervous system due to its unique structure and function.
Relevance to ADHD:
Visual processing is often affected in ADHD, with genes expressed in the retina playing roles in attention, sensory integration, and dopamine signaling, all of which influence ADHD-related behaviors.
Retina: Neural tissue in the eye that processes visual information.
Gene Expression Levels: TMEM30A (11.2), SGSM2 (9.5), ADGRL1 (9.2), ADGRL3 (8.8), NUAK1 (8.0), DRD4 (2.9), MC4R (1.2).
Relevance: Retinal activity connects to visual processing pathways, which are relevant given ADHD's links to altered sensory processing.
Parasympathetic Nervous System
Definition:
The parasympathetic nervous system is a branch of the autonomic nervous system responsible for conserving energy and maintaining the body's rest-and-digest state by regulating functions like heart rate, digestion, and relaxation.
Relevance to ADHD:
Dysregulation in the parasympathetic nervous system may contribute to emotional dysregulation, impulsivity, and difficulties with stress response seen in ADHD, highlighting its role in maintaining balance between arousal and relaxation.
Motor Neuron: Neurons that control muscle movement.
Gene Expression Levels: TMEM30A (10.5), ADGRL3 (10.2), ADGRL1 (9.4), NUAK1 (9.3), SGSM2 (8.6), MC4R (0.1), DRD4 (0.1).
Relevance: Impaired motor neuron signaling may contribute to motor coordination challenges in ADHD.
Sensory Neuron: Neurons that transmit sensory information to the CNS.
Gene Expression Levels: ADGRL1 (11.9), TMEM30A (11.6), SGSM2 (10.2), ADGRL3 (10.2), NUAK1 (9.4), DRD4 (2.9), MC4R (1.2).
Relevance: Sensory processing disruptions in ADHD may stem from altered sensory neuron activity.
Based on the information provided, including biological processes, pathways, psychiatric disorders, and tissue expression data, here's the ranking of ADHD genes from greatest to least relevance to ADHD. This ranking considers gene activity in key ADHD-related processes (e.g., synaptic plasticity, dopamine signaling) and tissue-specific expression (e.g., CNS regions):
1. ADGRL1
Relevance: High expression in ADHD-relevant CNS regions (e.g., hypothalamus: 11.4, cerebral cortex: 11.8), strong involvement in synaptic plasticity, glutamate signaling, and dopamine pathways.
Key Processes: Regulation of synaptic plasticity, neurotransmitter secretion, and neuron cell adhesion.
Psychiatric Disorders: Significant association with visual hallucinations, anxiety, and depression.
2. SGSM2
Relevance: Broad expression across CNS regions, involvement in multiple ADHD-related pathways (e.g., synaptic transmission, glutamatergic signaling).
Key Processes: Strong ties to neurotransmitter regulation, locomotory behavior, and synaptic plasticity.
Psychiatric Disorders: Implicated in visual hallucinations, anxiety, and social interaction deficits.
3. ADGRL3
Relevance: High expression in CNS tissues (e.g., cerebellum: 11.4, cerebral cortex: 10.9), significant involvement in synaptic transmission and glutamate receptor signaling.
Key Processes: Strongly linked to locomotory behavior, synaptic plasticity, and neurotransmitter regulation.
Psychiatric Disorders: Associated with visual hallucinations, startle response, and impaired social interactions.
4. TMEM30A
Relevance: Ubiquitous high expression in CNS tissues (e.g., astrocytes: 11.6, neurons: 11.1), involved in neurotransmitter transport and synaptic regulation.
Key Processes: Plays roles in neurotransmitter secretion, synaptic transmission, and cell adhesion.
Psychiatric Disorders: Associated with visual hallucinations, anxiety, and depression.
5. MC4R
Relevance: Lower expression compared to other genes but significant in dopamine-related pathways and ADHD-relevant behaviors like locomotion and exploration.
Key Processes: Involved in dopamine signaling, glutamatergic transmission, and synaptic plasticity.
Psychiatric Disorders: Associated with psychosis, delayed motor development, and emotional dysregulation.
6. NUAK1
Relevance: Moderate CNS expression and a supporting role in motor coordination, synaptic regulation, and neurotransmitter transport.
Key Processes: Linked to motor behaviors, neurotransmitter secretion, and axon guidance.
Psychiatric Disorders: Tied to motor impairments like difficulty running and climbing stairs.
7. DRD4
Relevance: Lower expression scores but directly tied to dopamine receptor signaling, which is highly relevant to ADHD symptoms.
Key Processes: Focused on dopamine pathways and short-term memory processes.
Psychiatric Disorders: Limited direct associations but relevant for ADHD through its critical role in dopamine signaling.
This ranking highlights ADGRL1, SGSM2, and ADGRL3 as the most relevant genes, given their strong expression in ADHD-related brain regions and involvement in critical pathways.
Connections Beyond ADHD: Genetic Overlaps and Broader Implications
ADHD, while a unique neurodevelopmental condition, shares genetic and biological mechanisms with other neurological and motor coordination disorders. One such example is ataxia, a condition characterized by motor coordination difficulties and impaired balance. By examining the genetic overlap between these conditions, we gain valuable insights into the shared pathways that contribute to their symptoms.
Shared Genes and Functions
1. ADGRL1 and ADGRL3 (Adhesion GPCRs):
These genes are involved in synaptic adhesion and neurotransmitter regulation. In ataxia, variants in these genes disrupt motor coordination and balance, while in ADHD, they contribute to traits like impulsivity and attention regulation through their effects on neural connectivity.
2. SGSM2 (Small GTPase Signaling Modulator 2):
SGSM2’s role in neurotransmitter transport and synaptic plasticity links it to both conditions. Disruptions in this gene affect motor functions in ataxia and cognitive regulation in ADHD.
3. TMEM30A (Transmembrane Protein 30A):
This gene maintains cell membrane asymmetry and facilitates neurotransmitter secretion. Variants can lead to motor coordination deficits in ataxia and dysregulated behavioral control in ADHD.
4. NUAK1 (NUAK Family Kinase 1):
Involved in axon guidance and motor control, NUAK1 disruptions manifest as gait and movement difficulties in ataxia and clumsiness or motor planning issues in ADHD.
5. MC4R (Melanocortin 4 Receptor):
MC4R impacts both reward processing and motor regulation. Its shared involvement highlights how motor and behavioral traits can arise from similar genetic disruptions.
Overlapping Pathways
1. Synaptic Plasticity:
Both ADHD and ataxia involve impairments in synaptic plasticity, which affects how neurons communicate and adapt. This underpins motor coordination deficits in ataxia and cognitive-behavioral dysregulation in ADHD.
2. Neurotransmitter Signaling:
Disruptions in dopamine, glutamate, and GABA signaling pathways are common to both conditions. For ataxia, these affect motor control, while in ADHD, they influence attention and emotional regulation.
3. Cerebellar Dysfunction:
The cerebellum, crucial for motor coordination in ataxia, also plays a role in ADHD by affecting timing, attention, and cognitive functions. Shared cerebellar pathways connect the two conditions.
Behavioral and Neurological Connections
Motor Coordination Issues:
Ataxia’s hallmark symptoms of impaired motor coordination overlap with the clumsiness and delayed motor milestones often seen in ADHD. Both may stem from shared disruptions in neural networks.
Cognitive Impairments:
Attention and executive function challenges are central to ADHD but may also appear in ataxia, highlighting common neural pathways involved in cognition.
Conclusion
Exploring the genetic overlap between ADHD and ataxia underscores the interconnected nature of neurological conditions. Understanding shared genes and pathways not only deepens our comprehension of ADHD but also opens the door to broader therapeutic strategies that address overlapping symptoms across disorders.
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