My Potential ADHD Risk Factors based on 2022 Published 'Genome-wide analyses of ADHD identify 27 risk loci'

I read a Genome Wide Association Study about the identification of 27  risk loci in connection to Attention Deficit Hyperactivity Disorder (ADHD).  It greatly interested me because I am a neurodivergent with Dyslexia, Dyspraxia, ADHD.  I also have Ataxia which is a rare neurological condition that involves problems with coordination like Dyspraxia does.

I was diagnosed as having inattentive type ADHD in my 30s. I believe that I have a combined type. I didn't get diagnosed as having ADHD in childhood because my other neurodivergent conditions were masking it. There was much more concern about my speech, auditory processing, and coordination problems.  I was spanked a lot in my special education childhood years, and so that influenced me to have adequate behavior.  Instead of running around in the classroom, I was running around in my head. I saved my hyperactivity for outside the classroom except for fidgeting and talking a lot in classroom. I  see ADHD traits in my mother and they run strongly in my maternal grandfather's side of the family. From what my mother and paternal Aunt Carrie told me, my father had them too. 

I have done a blog post about DRD4 (Dopamine Receptor D4) which I have some variant in that include a 5 Prime Untranslated Region (5'UTR) Promoter variant that I inherited from my mother that is reported in ClinVar as Uncertain Significance for hereditary ADHD. DRD4 has been the top gene associated with ADHD.  It also has been linked to novelty seeking. I don't have any DRD4 variants with a condition allele frequency of less than 5% which is the maximum that I use for ADHD, and so I think that my DRD4 variants are more about novelty seeking personality than ADHD. My DRD4 5'UTR Promoter variant has a condition allele frequency of less than 10% which is the maximum that I use for Dyslexia.  DRD4 has been considered to be linked to both ADHD and Dyslexia.  It is a gene listed in GWAS about Dyslexia-ADHD co-morbidity. I will be posting a blog post based on that study. 

https://neurodivergence.blogspot.com/2024/01/the-drd4-dopamine-receptor-d4-gene.html

Abstract 

Attention deficit hyperactivity disorder (ADHD) is a prevalent childhood neurodevelopmental disorder with a major genetic component. Here we present a GWAS meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genomewide significant loci, which is more than twice the number previously reported. Fine-mapping risk loci highlighted 76 potential risk genes enriched in genes expressed in brain, particularly the frontal cortex, and in early brain development. Overall, ADHD genetic risk was associated with several brain- specific neuronal sub-types and especially midbrain dopaminergic neurons. In a subsample of 17,896 exome-sequenced individuals, we identified an increased load of rare protein-truncating variants in cases for a set of risk genes enriched with likely causal common variants, potentially implicating SORCS3 in ADHD by both common and rare genetic variation . We found ADHD to be highly polygenic, with around seven thousand variants explaining 90% of the SNP heritability. Bivariate gaussian mixture modeling estimated that more than 84% of ADHD- influencing variants are shared with other psychiatric disorders (autism, schizophrenia and depression) and related phenotypes (e.g., educational attainment), when both concordant and discordant variants are considered. Additionally, we demonstrated that common variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention. 

https://diposit.ub.edu/dspace/bitstream/2445/197326/1/724648.pdf

I looked at variants with Condition allele frequency of no more than 5%.

They are based on Grpmax Filtering AF in gnomAD v4

This annotation can be used for filtering variants by allele frequency against a disease-specific threshold that can be set for each disease (e.g. BA1 in the 2015 ACMG/AMP guidelines). In this case the filtering allele frequency (FAF) is the maximum credible genetic ancestry group AF (e.g. the lower bound of the 95% confidence interval (CI)). If the FAF is above the disease-specific threshold, then the observed AC is not compatible with pathogenicity. See http://cardiodb.org/allelefrequencyapp/ and Whiffin et al. 2017 for additional information.

https://gnomad.broadinstitute.org/help/faf

I looked for variants with Combined Annotation Dependent Depletion (CADD) scores of at least 10, and so the variants are predicted to be in the top 10% of the most deleterious. 

My focus was mainly on the 5 Prime Untranslated Region, 3 Prime Untranslated Region, and Promoter because they are critical regulatory features in genes.  I used VEP to see if the variants involve these regulatory features.

exceptions in CADD Scores: 5 Prime Untranslated Region (5'UTR) perturbing variants (Premature Start Codon Gain, Premature Start Codon Loss, Premature Stop Codon Gain, Premature Stop Codon Loss, uORF Frameshift)

In molecular genetics, an untranslated region (or UTR) refers to either of two sections, one on each side of a coding sequence on a strand of mRNA. If it is found on the 5' side, it is called the 5' UTR (or leader sequence), or if it is found on the 3' side, it is called the 3' UTR (or trailer sequence). mRNA is RNA that carries information from DNA to the ribosome, the site of protein synthesis (translation) within a cell. The mRNA is initially transcribed from the corresponding DNA sequence and then translated into protein. However, several regions of the mRNA are usually not translated into protein, including the 5' and 3' UTRs.

Although they are called untranslated regions, and do not form the protein-coding region of the gene, uORFs located within the 5' UTR can be translated into peptides.^[1]

The 5' UTR is upstream from the coding sequence. Within the 5' UTR is a sequence that is recognized by the ribosome which allows the ribosome to bind and initiate translation. The mechanism of translation initiation differs in prokaryotes and eukaryotes. The 3' UTR is found immediately following the translation stop codon. The 3' UTR plays a critical role in translation termination as well as post-transcriptional modification.^[2]

These often long sequences were once thought to be useless or junk mRNA that has simply accumulated over evolutionary time. However, it is now known that the untranslated region of mRNA is involved in many regulatory aspects of gene expression in eukaryotic organisms. The importance of these non-coding regions is supported by evolutionary reasoning, as natural selection would have otherwise eliminated this unusable RNA.

It is important to distinguish the 5' and 3' UTRs from other non-protein-coding RNA. Within the coding sequence of pre-mRNA, there can be found sections of RNA that will not be included in the protein product. These sections of RNA are called introns. The RNA that results from RNA splicing is a sequence of exons. The reason why introns are not considered untranslated regions is that the introns are spliced out in the process of RNA splicing. The introns are not included in the mature mRNA molecule that will undergo translation and are thus considered non-protein-coding RNA.

https://en.wikipedia.org/wiki/Untranslated_region

Ensembl data

Regions that are predicted to regulate gene expression are called Regulatory features in Ensembl. The different types of regulatory features annotated include:

Promoters (regions at the 5' end of genes where transcription factors and RNA polymerase bind to initiate transcription)

Promoter flanking regions (transcription factor binding regions that flank the above)

Enhancers (regions that bind transcription factors and interact with promoters to stimulate transcription of distant genes)

CTCF binding sites (regions that bind CTCF, the insulator protein that demarcates open and closed chromatin)

Transcription factor binding sites (sites which bind transcription factors, for which no other role can be determined as yet)

Open chromatin regions (regions of spaced out histones, making them accessible to protein interactions)

https://grch37.ensembl.org/info/genome/funcgen/regulatory_features.html

Ensembl youtube video playlist  Gene Regulation - 8 videos 

https://www.youtube.com/playlist?list=PLqB8Yx1tGBMbFtUj_3rYxoasRiMqe3ltO

Genes in 2022 GWAS study

PTPRF

ELOVL1   

MED8

B4GALT2 

NBEAL1 

CAMKV   

RHOA   

MON1A  

CCDC71  

HYAL3 

FOXP1   

LSM6 

COL19A1 

KIZ

GNA12  

CALN1 

FOXP2  

RPL8  

ARHGAP39  

PPP1R16A   

LRRC14 

SORCS3  

PNPLA2   

CDH8   

DCC   

CALN1(Calneuron 1) is listed in both the ADHD GWAS and Dyslexia GWAS, and that points to a genetic overlap between Dyslexia and ADHD. The gene also has connection to deafness, and so it could play a part in auditory processing deficits which are found in many people with Dyslexia.  I have two CALN1 intronic variants that are listed in both my Dyslexia GWAS blog post and this ADHD GWAS blog post.  

https://neurodivergence.blogspot.com/2024/02/my-potential-dyslexia-risk-factors.html

ELOVL1 (ELOVL Fatty Acid Elongase 1) listed in the ADHD GWAS has a connection to Spinocerebellar Ataxia, and that points to a genetic overlap between Ataxia and ADHD. I have a rare 3 Prime Untranslated Region (3'UTR) ELOVL1 variant.  There are studies about Dyslexia, Dyspraxia, and ADHD being linked to fatty acid deficiencies. 

My Sequencing Genomic Data

FOXP2

FOXP2 (Forkhead Box P2) is a Protein Coding gene. Diseases associated with FOXP2 include Isolated Childhood Apraxia Of Speech and Speech And Communication Disorders. Among its related pathways are Pathways affected in adenoid cystic carcinoma and Wnt / Hedgehog / Notch. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and sequence-specific DNA binding. An important paralog of this gene is FOXP4.

This gene encodes a member of the forkhead/winged-helix (FOX) family of transcription factors. It is expressed in fetal and adult brain as well as in several other organs such as the lung and gut. The protein product contains a FOX DNA-binding domain and a large polyglutamine tract and is an evolutionarily conserved transcription factor, which may bind directly to approximately 300 to 400 gene promoters in the human genome to regulate the expression of a variety of genes. This gene is required for proper development of speech and language regions of the brain during embryogenesis, and may be involved in a variety of biological pathways and cascades that may ultimately influence language development. Mutations in this gene cause speech-language disorder 1 (SPCH1), also known as autosomal dominant speech and language disorder with orofacial dyspraxia. Multiple alternative transcripts encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=FOXP2

rs940890058  7-114642502-G-A     data not available for my mother

Missense variant, 3'UTR 

2 out of 1,613,666 (0.0001239%) Condition allele frequency is 0.000444%

25.0

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA164868669

MON1A

MON1A (MON1 Homolog A, Secretory Trafficking Associated) is a Protein Coding gene. Diseases associated with MON1A include Endometriosis Of Pelvic Peritoneum and Hermansky-Pudlak Syndrome. Among its related pathways are Vesicle-mediated transport and Rab regulation of trafficking. An important paralog of this gene is MON1B.

Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in protein secretion. Predicted to act upstream of or within cellular iron ion homeostasis and protein transport. Part of Mon1-Ccz1 complex. [provided by Alliance of Genome Resources, Apr 2022]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=MON1A

 rs148809365  3-49913318-C-T     not available for my mother

Missense

809 out of 1613606 (0.05014%) Condition allele frequency is 0.869%

19.3

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2409969

ELOVL1

ELOVL1 (ELOVL Fatty Acid Elongase 1) is a Protein Coding gene. Diseases associated with ELOVL1 include Ichthyotic Keratoderma, Spasticity, Hypomyelination, And Dysmorphic Facial Features and Spinocerebellar Ataxia 38. Among its related pathways are Fatty acid metabolism and docosahexaenoate biosynthesis III (mammals). Gene Ontology (GO) annotations related to this gene include fatty acid elongase activity. An important paralog of this gene is ELOVL7.

Enables fatty acid elongase activity. Involved in fatty acid biosynthetic process and sphingolipid biosynthetic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=ELOVL1

 rs187826081   1-43363667-T-G

 3'UTR Variant

 158 out of 536,860  (0.02943%) Condition allele frequency is 0.2473%

19.3   

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA21623628

RHOA

RHOA (Ras Homolog Family Member A) is a Protein Coding gene. Diseases associated with RHOA include Ectodermal Dysplasia With Facial Dysmorphism And Acral, Ocular, And Brain Anomalies and Linear Hypopigmentation And Craniofacial Asymmetry With Acral, Ocular And Brain Anomalies. Among its related pathways are Semaphorin interactions and p75 NTR receptor-mediated signalling. Gene Ontology (GO) annotations related to this gene include GTP binding and myosin binding. An important paralog of this gene is RHOC.

This gene encodes a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. Overexpression of this gene is associated with tumor cell proliferation and metastasis. Multiple alternatively spliced variants have been identified. [provided by RefSeq, Sep 2015]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=RHOA

rs72554687  3-49359207-T-C

3'UTR Variant in Promoter 

1,092 out of 188,524 (0.5792%) Condition allele frequency is 2.283%

12.7   

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA74506865

CDH8

CDH8 (Cadherin 8) is a Protein Coding gene. Diseases associated with CDH8 include Ectodermal Dysplasia, Ectrodactyly, And Macular Dystrophy Syndrome and Craniofacial-Deafness-Hand Syndrome. Among its related pathways are Regulation of CDH11 Expression and Function and Cell junction organization. Gene Ontology (GO) annotations related to this gene include calcium ion binding. An important paralog of this gene is CDH11.

This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. The extracellular domain consists of 5 subdomains, each containing a cadherin motif, and appears to determine the specificity of the protein's homophilic cell adhesion activity. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. This particular cadherin is expressed in brain and is putatively involved in synaptic adhesion, axon outgrowth and guidance. [provided by RefSeq, Jul 2008]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=CDH8

rs148649841  16-62036881-G-A

2KB Upstream Variant in Promoter 

837 out of 152,600 (0.5485%) Condition allele frequency is 0.7705%           

10.3

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA283044622

CALN1

CALN1 (Calneuron 1) is a Protein Coding gene. Diseases associated with CALN1 include D-Glyceric Aciduria and Deafness, Autosomal Recessive 39. Gene Ontology (GO) annotations related to this gene include calcium ion binding. An important paralog of this gene is CABP7.

This gene encodes a protein with high similarity to the calcium-binding proteins of the calmodulin family. The encoded protein contains two EF-hand domains and potential calcium-binding sites. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=CALN1

rs76435245   7-72441867-C-T

Intronic Variant 

440 out of 152,066 (0.2893%) Condition allele frequency is 0.956%

11.4  

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA160841942

rs112952850   7-72135505-T-C

Intronic Variant 

2,075 out of 152,330 (1.362%) Condition allele frequency is 4.502%

9.99 

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA160795091