Cohort profile: Extended Cohort for E-health, Environment and DNA (EXCEED).

[First paragraph] EXCEED aims to develop understanding of the genetic, environmental and lifestyle-related causes of health and disease. Cohorts like EXCEED, with broad consent to study multiple phenotypes related to onset and progression of disease and drug response, have a role to play in medicines development, by providing genetic evidence that can identify, support or refute putative drug efficacy or identify possible adverse effects.1 Furthermore, such cohorts are well suited to the study of multimorbidity

Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants

Isolated populations are emerging as a powerful study design in the search for low-frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece and the Mylopotamos villages (HELIC-MANOLIS) in Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort, we observe an enrichment of missense variants among the variants that have drifted up in frequency by more than fivefold. In the Pomak cohort, we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example, with mean corpuscular volume (rs7116019, P=2.3 × 10−26). We replicate this association in a second set of Pomak samples (combined P=2.0 × 10−36). We demonstrate significant power gains in detecting medical trait associations

Contributing studies and sample characteristics.

<p>Contributing studies and sample characteristics.</p

Global meta-analysis results with p≤0.001.

<p>EA - effect allele; EAF - effect allele frequency; SE - standard error; P - p-value; I²- measure of heterogeneity; N - total number of samples.</p

Global meta-analysis results for the rs9939609 <i>FTO</i> SNP.

<p>EA - effect allele; EAF - effect allele frequency; SE - standard error; P - p-value; I²- measure of heterogeneity; N - total number of samples.</p

Study design. Each step includes non-overlapping, independent datasets.

<p>Study design. Each step includes non-overlapping, independent datasets.</p

Manhattan and QQ plots based on meta-analyses results of the discovery panel: a) combined set - age adjusted, b) combined set - age and BMI adjusted.

<p>Manhattan and QQ plots based on meta-analyses results of the discovery panel: a) combined set - age adjusted, b) combined set - age and BMI adjusted.</p

Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (Phase 1) imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5x10-8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1, AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered

Additional file 3: of Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Video S1. (Quicktime) Video to illustrate the DORV phenotype finding in an Adamts6 mutant heart. (MOV 1983 kb

Additional file 2: of Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Figure S1. Manhattan plot for European and African-American ancestry single variant analysis. Figure S2. Quantile-quantile plot for European and African-American ancestry single variant analysis. Figure S3. Manhattan plot for EA single variant analysis. Figure S4. QQ plot for EA single variant analysis. Figure S5. Manhattan plot for AA single variant analysis. Figure S6. Quantile-quantile plot for AA single variant analysis. Figure S7. Miami plot European and African-American ancestry sex-stratified single variant analysis. Figure S8. Quantile-quantile plots for European and African-American ancestry sex-stratified single variant analyses. Figure S9. Normal morphology of adult Adamts6 heterozygous hearts. (DOCX 4290 kb