Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10−6). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ~10% of the cases (P = 4.38 × 10−10) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

Objective:Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology.Method:The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium.Results:The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder.Conclusions:These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

Objective-To assess the impact of diabetic retinopathy (DR) and its severity on health-related quality of life (HRQOL) in a population-based sample of Latinos with type 2 diabetes mellitus. Design-Cross-sectional population-based study, the Los Angeles Latino Eye Study (LALES). Participants-1,064 LALES participants with diabetes mellitus.Methods-HRQOL was measured by the 25 item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and the Medical Outcomes Study 12-Item Short Form Health Survey (SF-12). DR was assessed by masked standardized grading of stereoscopic photographs from 7 standard fields. Severity of DR in eyes was graded using a modified Airlie House classification. The severity scores from each eye were then concatenated to create a single per person grade ranging from 1(no DR in either eye) to 15 (bilateral PDR). Multiple linear regression analyses were performed to determine the independent relationship between severity of DR and HRQOL after adjusting for covariates. Main Outcome Measures-NEI-VFQ-25 and SF-12 scores.Results-More severe DR was associated with worse HRQOL scores on all of the NEI VFQ-25 and SF-12 subscales (P<0.05). Individuals with DR from grade 2 (minimum NPDR) through grade 8 (unilateral moderate NPDR) show a modest decline in HRQOL. However, the decline become significantly steeper between steps 8 (unilateral moderate NPDR) and 9-15 (bilateral moderate NPDR to bilateral PDR). The domains with the most significant impact were for vision-related daily activities, dependency and mental health. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptOphthalmology. Author manuscript; available in PMC 2012 April 1. Conclusion-Greater severity of DR was associated with lower general and vision-specific HRQOL. Persons with bilateral moderate NPDR had the most substantial decrease in quality of life compared to those with less severe DR. The prevention of incident DR and more importantly its progression from unilateral to bilateral NPDR is likely to have a positive impact on a person's HRQOL and should be considered an important goal in management of individuals with diabetes mellitus.

Purpose-To examine the relationship between the prevalence of open-angle glaucoma (OAG) and intraocular pressure (IOP) and the impact of central corneal thickness (CCT) on this relationship.Design-Population based cross-sectional study.Methods-The study cohort consisted of 5970 participants from the Los Angeles Latino Eye Study (LALES) with no history of glaucoma treatment and with complete ophthalmic examination data. The relationship between the prevalence of OAG and IOP was contrasted across persons with CCT designated as thin, normal or thick.Results-Prevalence of OAG was exponentially related to IOP. When stratified by CCT, persons with thin CCT had a significantly higher prevalence of OAG than did those with normal or thick CCT's at all levels of IOP. Adjusting each IOP individually for CCT did not impact significantly the relationship between the prevalence of OAG and IOP.Conclusions-These findings suggest that adjusting for the impact of CCT on IOP by correction algorithms is not necessary in a population analysis of glaucoma prevalence; CCT and other associated corneal properties, however, are important independent risk factors for the prevalence of OAG.

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