Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Bipolar disorder risk alleles in children with ADHD.

Bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) may share common genetic risk factors as indicated by the high co-morbidity of BD and ADHD, their phenotypic overlap especially in pediatric populations, the high heritability of both disorders, and the co-occurrence in families. We therefore examined whether known polygenic BD risk alleles are associated with ADHD. We chose the eight best SNPs of the recent genome-wide association study (GWAS) of BD patients of German ancestry and the nine SNPs from international GWAS meeting a 'genome-wide significance' level of α = 5 × 10(-8). A GWAS was performed in 495 ADHD children and 1,300 population-based controls using HumanHap550v3 and Human660 W-Quadv1 BeadArrays. We found no significant association of childhood ADHD with single BD risk alleles surviving adjustment for multiple testing. Yet, risk alleles for BD and ADHD were directionally consistent at eight of nine loci with the strongest support for three SNPs in or near NCAN, BRE, and LMAN2L. The polygene analysis for the BP risk alleles at all 14 loci indicated a higher probability of being a BD risk allele carrier in the ADHD cases as compared to the controls. At a moderate power to detect association with ADHD, if true effects were close to estimates from GWAS for BD, our results suggest that the possible contribution of BD risk variants to childhood ADHD risk is considerably lower than for BD. Yet, our findings should encourage researchers to search for common genetic risk factors in BD and childhood ADHD in future studies.

Diabetes incidence does not differ between subjects with and without high depressive symptoms--5-year follow-up results of the Heinz Nixdorf Recall Study.

AIMS: Cross-sectional studies have consistently reported evidence for an association between diabetes and depressive disorders. However, only limited prospective studies have examined this association, reporting conflicting results. In a population-based cohort study, we compared cumulative incidences of diabetes between participants with and without high depressive symptoms. METHOD: We analysed the 5-year follow-up data from the German Heinz Nixdorf Recall study of 3547 participants without diabetes at baseline [mean age 58.8 (sd 7.6) years, 47.5% male]. Depressive symptoms were defined using the Centre for Epidemiologic Studies Depression scale (cut point ≥ 17). Diabetes (diagnosed or previously undetected) was identified by self-reported physician-diagnosed diabetes, medication and high blood glucose levels. We estimated 5-year cumulative incidences with 95% confidence intervals and fitted multiple logistic regression models to calculate the odds ratios, adjusted for age, sex, physical activity, smoking, living with or without partner, and educational level. RESULTS: The cumulative incidence of diabetes was 9.2% (95% CI 6.3-12.8) in participants with high depressive symptoms at baseline and 9.0% (95% CI 8.0-10.0) in participants without these symptoms. The age- and sex-adjusted odds ratio of diabetes in participants with depressive symptoms compared with those without was 1.13 [95% CI 0.77-1.68; fully adjusted 1.11 (95% CI 0.74-1.65)]. These results did not substantially change in several additional sensitivity analyses. CONCLUSION: Our study did not show a significantly increased risk of developing diabetes in individuals with high depressive symptoms compared with those without high depressive symptoms during a 5-year follow-up period.