Investigating the Contribution of Common Genetic Variants to the Risk and Pathogenesis of ADHD

Abstract

Objective:A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs.Method:The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD.Results:No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS.Conclusions:Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.

Polygenic risk of Parkinson disease is correlated with disease age at onset

“…In accordance with the pattern seen in studies of other complex diseases shown to have a polygenic signal,18, 24, 25, 26 restricting our analysis to SNPs that met the lowest association test probability value thresholds ( p T ) in the discovery sample ( p T  < 10 −4 , p T  < 10 −3 , p T  < 0.01, p T  < 0.05) did not identify a systematic significant inflation in the polygenic scores of the PD cases of the replication samples ( p  > 0.05). Rather, our most significant evidence was observed when SNPs with p T  ≤ 0.5 in the UK sample were included where probability values for a significant inflation in the polygenic scores ranged between 4.42 × 10 −4 and 8.22 × 10 −5 (see Table 1).…”

Identifying mechanisms that underlie links between COMT genotype and aggression in male adolescents with ADHD

“…Genotype data for the COMT Val158Met SNP (rs 4680) had been generated on most previous participants using the GWAS Illumina 660K array (Stergiakouli et al., 2012). For the remainder who had not been genotyped, genotyping was performed using Snapshot single‐base extension assays (Life Technologies, Carlsbad, CA).…”

Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study

“…Recent research indicates that ADHD is associated with a significant overlap of biological pathways enriched for both common variants and rare CNVs 8,10,11 , suggesting that perturbation in these pathways is critical for conferring risk to ADHD. Thus we restricted the search space for rare SNVs and InDels that may be associated with ADHD by focusing on those genes implicated in previous research.…”

“…Our sample comprised 152 ADHD cases and 188 controls from amongst subjects recruited in the Republic of Ireland 11,16 . Recruitment and ascertainment of ADHD cases was approved by the Eastern Regional Health Authority research ethics committee and written informed consent was obtained from parents.…”