Genome‐wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations

Abstract

Attention deficit hyperactivity disorder (ADHD) is a complex condition with environmental and genetic etiologies. Up to this point, research has identified genetic associations with candidate genes from known biological pathways. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. We generated six quantitative phenotypes from 18 ADHD symptoms to be used in genome-wide association analyses. With the PBAT screening algorithm, we identified 2 SNPs, rs6565113 and rs552655 that met the criteria for significance within a specified phenotype. These SNPs are located in intronic regions of genes CDH13 and GFOD1, respectively. CDH13 has been implicated previously in substance use disorders. We also evaluated the association of SNPs from a list of 37 ADHD candidate genes that was specified a priori. These findings, along with association Pvalues with a magnitude less than 10 À5 , are discussed in this manuscript. Seventeen of these candidate genes had association P-values lower then 0.01: SLC6A1, SLC9A9, HES1, ADRB2, HTR1E, DDC, ADRA1A, DBH, DRD2, BDNF, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, SNAP25, and COMT. Among the candidate genes, SLC9A9 had the strongest overall associations with 58 association test P-values lower than 0.01 and multiple association P-values at a magnitude of 10 À5 in this gene. In sum, these findings identify novel genetic associations at viable ADHD candidate genes and provide confirmatory evidence for associations at previous candidate genes. Replication of these results is necessary in order to confirm the proposed genetic variants for ADHD.

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

“…[46][47][48][49][50][51][52][53][54][55] In addition, some cadherins have been specifically identified in genome-wide association scans of ADHD, addiction and neuroticism personality features. [56][57][58] Of related interest, variants in CDH2 and other cadherins have been widely found to CDH2 variants in OCD and TD PR Moya et al be associated with various cancers 16,59,60 and, specifically, upregulated CDH2 has been associated with transepithelial spreading of melanoma and pancreatic cancer together with rapid recurrence of cancer. [61][62][63] In summary, although CDH2 is an attractive candidate gene based on the CCD study findings, 11 the present results suggest that these CDH2 variants are not disease-causing by themselves.…”

Genome-wide linkage analysis in a Dutch multigenerational family with attention deficit hyperactivity disorder

“…42 It is remarkable that in a clinically and genetically heterogeneous disorder such as ADHD, overlapping genomic regions are reported by studies conducted in different populations, using different assessment, genotyping and analysis strategies. Hopefully, the ongoing GWA studies [18][19][20] will help to highlight specific SNPs and genes within the broad areas detected by our, as well as other, linkage studies. In conclusion, we performed a GWLA in a relatively large Dutch family with eight ADHD patients and found two (replicated) loci showing suggestive evidence of linkage on chromosomes 7p and 14q.…”

“…13,17 Since recently, genome-wide association studies (GWA) are becoming available for ADHD. [18][19][20] Eventually, they will lead to the identification of novel genes or pathways, as genome-wide studies do not rely on current biological knowledge. To date, eight genome-wide linkage analyses (GWLA) have been performed in ADHD.…”

Old Obstacles on New Horizons: The Challenge of Implementing Gene X Environment Discoveries in Schizophrenia Research

“…The apparent discord between candidate-gene and GWAS findings is typical for most of Psychiatry, with very few exceptions 111 (convergent GWAS and candidate-gene findings in Schizophrenia are noted in table 2). If anything, GWAS has diverted attention towards less-obvious genomic points of interest, many of which lie within the non-coding domain.…”