Genome‐wide association study in German patients with attention deficit/hyperactivity disorder

Abstract

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.

BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations

“…14). In addition, SNPs in this region have also been implicated in attention deficit/hyperactivity disorder (ADHD), another condition thought to be due to underlying alterations in neurodevelopment (23). Therefore, by studying rare patients with BCL11A haploinsufficiency in concert with orthogonal genetic data of human neurodevelopmental disorders, we were able to strongly implicate BCL11A as a key gene whose function is necessary for normal human neurologic function and where alterations underlie a number of neuropsychiatric disorders.…”

Genome-Wide Association Studies on Attention Deficit Hyperactivity Disorder

“…ADHD is considered to be a highly heritable disorder from the previous family-based study [1]. The heritability of this disease is about 0.8 [2]. However, it is difficult to identify genes or susceptibility loci associated with the disorder.…”

“…Recently, large scale genome-wide association studies [2][3][4][5][6][7][8][9][10] have been applied to identify novel ADHD risk genes using either unrelated case-control or family-based design (Table 1). An unrelated case-control GWAS was conducted on adult ADHD patients using Affymetrix Human Mapping 500K SNP microarray by Lesch et al [3].…”

“…Hinney et al [2] performed an unrelated case-control on 495 German ADHD children/adolescents and 1,300 controls. 11,917 X-chromosomal and 487,484 autosomal SNPs were investigated and the lowest p-value was 8.37 × 10 -7 at the SNP rs2556378.…”

Addendum: Genome‐wide association study in German patients with attention deficit/hyperactivity disorder

“…

We noted that SNP rs5016282, the second best hit of our genome-wide association study (GWAS) [Hinney et al, 2011], is most likely wrongly located to the gene GRM5. The SNP thus needs to be removed from the paper.

After our publication we detected that the genotypes of SNP rs5016282 could not be confirmed by Sanger re-sequencing.

…”