Detection and correction of artefacts in estimation of rare copy number variants and analysis of rare deletions in type 1 diabetes.

Copy number variants (CNVs) have been proposed as a possible source of 'missing heritability' in complex human diseases. Two studies of type 1 diabetes (T1D) found null associations with common copy number polymorphisms, but CNVs of low frequency and high penetrance could still play a role. We used the Log-R-ratio intensity data from a dense single nucleotide polymorphism (SNP) array, ImmunoChip, to detect rare CNV deletions (rDELs) and duplications (rDUPs) in 6808 T1D cases, 9954 controls and 2206 families with T1D-affected offspring. Initial analyses detected CNV associations. However, these were shown to be false-positive findings, failing replication with polymerase chain reaction. We developed a pipeline of quality control (QC) tests that were calibrated using systematic testing of sensitivity and specificity. The case-control odds ratios (OR) of CNV burden on T1D risk resulting from this QC pipeline converged on unity, suggesting no global frequency difference in rDELs or rDUPs. There was evidence that deletions could impact T1D risk for a small minority of cases, with enrichment for rDELs longer than 400 kb (OR = 1.57, P = 0.005). There were also 18 de novo rDELs detected in affected offspring but none for unaffected siblings (P = 0.03). No specific CNV regions showed robust evidence for association with T1D, although frequencies were lower than expected (most less than 0.1%), substantially reducing statistical power, which was examined in detail. We present an R-package, plumbCNV, which provides an automated approach for QC and detection of rare CNVs that can facilitate equivalent analyses of large-scale SNP array datasets.

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

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.

Severity of diabetic retinopathy and health-related quality of life: the Los Angeles Latino Eye Study.

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 (DM). DESIGN: Cross-sectional population-based study, the Los Angeles Latino Eye Study (LALES). PARTICIPANTS: We included 1064 LALES participants with DM. METHODS: We measured HRQOL 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). We assessed DR 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: Scores on the NEI-VFQ-25 and SF-12. 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 nonproliferative diabetic retinopathy [NPDR]) through grade 8 (unilateral moderate NPDR) show a modest decline in HRQOL. However, the decline becomes 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. CONCLUSIONS: 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 with those with less severe DR. The prevention of incident DR and, more important, 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 DM.

Variation in genetic admixture and population structure among Latinos: the Los Angeles Latino eye study (LALES).

BACKGROUND: Population structure and admixture have strong confounding effects on genetic association studies. Discordant frequencies for age-related macular degeneration (AMD) risk alleles and for AMD incidence and prevalence rates are reported across different ethnic groups. We examined the genomic ancestry characterizing 538 Latinos drawn from the Los Angeles Latino Eye Study [LALES] as part of an ongoing AMD-association study. To help assess the degree of Native American ancestry inherited by Latino populations we sampled 25 Mayans and 5 Mexican Indians collected through Coriell's Institute. Levels of European, Asian, and African descent in Latinos were inferred through the USC Multiethnic Panel (USC MEP), formed from a sample from the Multiethnic Cohort (MEC) study, the Yoruba African samples from HapMap II, the Singapore Chinese Health Study, and a prospective cohort from Shanghai, China. A total of 233 ancestry informative markers were genotyped for 538 LALES Latinos, 30 Native Americans, and 355 USC MEP individuals (African Americans, Japanese, Chinese, European Americans, Latinos, and Native Hawaiians). Sensitivity of ancestry estimates to relative sample size was considered. RESULTS: We detected strong evidence for recent population admixture in LALES Latinos. Gradients of increasing Native American background and of correspondingly decreasing European ancestry were observed as a function of birth origin from North to South. The strongest excess of homozygosity, a reflection of recent population admixture, was observed in non-US born Latinos that recently populated the US. A set of 42 SNPs especially informative for distinguishing between Native Americans and Europeans were identified. CONCLUSION: These findings reflect the historic migration patterns of Native Americans and suggest that while the 'Latino' label is used to categorize the entire population, there exists a strong degree of heterogeneity within that population, and that it will be important to assess this heterogeneity within future association studies on Latino populations. Our study raises awareness of the diversity within "Latinos" and the necessity to assess appropriate risk and treatment management.