Exome chip analyses in adult attention deficit hyperactivity disorder

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E−06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E−08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E−07); the PSD locus (P=7.58E−08) and ZCCHC4 locus (P=1.79E−06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E−05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

“…The cumulative effect of common and rare variants in selected genes and gene-sets was tested using the independent, recently published IMpACT exome-chip data set (Supplementary Methods; [22]). Statistical analyses were performed using the Multi-marker Analysis of GenoMic Annotation (MAGMA) software package (version 1.02; http://ctglab.nl/software/magma [40]) and the SNP-wide mean model for gene-based association analysis (for detailed description see Supplementary Methods).…”

“…a No variants were observed in the ANP32B gene in IMpACT exome-chip data. Gene-set-based association analysis used meta-analytic exome-chip data from 9365 individuals (1846 ADHD patients and 7519 controls [22]). …”

“…Gene-set analysis was performed based on this list using exome-chip data from an independent sample of 1846 adults with persistent ADHD and 7519 controls [22]. Following testing of the overall gene-set (24 genes), we also tested gene-sets resulted from each family separately (Table 2).…”

“…More evidence for involvement of less frequent genetic variants with potentially larger effect sizes comes e.g. from genome-wide studies of copy number variants (CNVs) [17][18][19][20][21] and initial exomechip [22] and whole-exome sequencing (WES) work [23,24]. In addition, WES has been successful in identifying rare risk alleles for other neurodevelopmental/ psychiatric disorders, such as autism spectrum disorders (ASDs) and schizophrenia (e.g.…”

“…Based on the WES applied to subsets of family members, we selected rare variants present in all (suggestive) linkage regions in each family. In line with the polygenic nature of ADHD, in which both common and rare genetic variants are likely to contribute to disease etiology, we subsequently used the extracted gene-sets to analyze the cumulative role of common and rare variants in persistent ADHD in an independent exome-chip data set (IMpACT consortium; N = 9365 [22]). …”