Dataset Information

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

ABSTRACT:

Aims/hypothesis

Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes.

Methods

The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p?ResultsExome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p?=?8.5?×?10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p?=?1.2?×?10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p?=?8.2?×?10(-10)).

Conclusions/interpretation

We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

SUBMITTER: Albrechtsen A

PROVIDER: S-EPMC3536959 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Publications

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

Albrechtsen A A Grarup N N Li Y Y Sparsø T T Tian G G Cao H H Jiang T T Kim S Y SY Korneliussen T T Li Q Q Nie C C Wu R R Skotte L L Morris A P AP Ladenvall C C Cauchi S S Stančáková A A Andersen G G Astrup A A Banasik K K Bennett A J AJ Bolund L L Charpentier G G Chen Y Y Dekker J M JM Doney A S F AS Dorkhan M M Forsen T T Frayling T M TM Groves C J CJ Gui Y Y Hallmans G G Hattersley A T AT He K K Hitman G A GA Holmkvist J J Huang S S Jiang H H Jin X X Justesen J M JM Kristiansen K K Kuusisto J J Lajer M M Lantieri O O Li W W Liang H H Liao Q Q Liu X X Ma T T Ma X X Manijak M P MP Marre M M Mokrosiński J J Morris A D AD Mu B B Nielsen A A AA Nijpels G G Nilsson P P Palmer C N A CN Rayner N W NW Renström F F Ribel-Madsen R R Robertson N N Rolandsson O O Rossing P P Schwartz T W TW Slagboom P E PE Sterner M M Tang M M Tarnow L L Tuomi T T van't Riet E E van Leeuwen N N Varga T V TV Vestmar M A MA Walker M M Wang B B Wang Y Y Wu H H Xi F F Yengo L L Yu C C Zhang X X Zhang J J Zhang Q Q Zhang W W Zheng H H Zhou Y Y Altshuler D D 't Hart L M LM Franks P W PW Balkau B B Froguel P P McCarthy M I MI Laakso M M Groop L L Christensen C C Brandslund I I Lauritzen T T Witte D R DR Linneberg A A Jørgensen T T Hansen T T Wang J J Nielsen R R Pedersen O O

Diabetologia 20121119 2

<h4>Aims/hypothesis</h4>Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes.<h4>Methods</h4>The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphi ...[more]

PMID: 23160641

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Project description:PurposeDemographic, environmental, and genetic risk factors for age-related macular degeneration (AMD) have been identified; however, a substantial portion of the variance in AMD disease risk and heritability remains unexplained. To identify AMD risk variants and generate hypotheses for future studies, we performed whole exome sequencing for 75 individuals whose phenotype was not well predicted by their genotype at known risk loci. We hypothesized that these phenotypically extreme individuals were more likely to carry rare risk or protective variants with large effect sizes.MethodsA genetic risk score was calculated in a case-control set of 864 individuals (467 AMD cases, 397 controls) based on 19 common (≥1% minor allele frequency, MAF) single nucleotide variants previously associated with the risk of advanced AMD in a large meta-analysis of advanced cases and controls. We then selected for sequencing 39 cases with bilateral choroidal neovascularization with the lowest genetic risk scores to detect risk variants and 36 unaffected controls with the highest genetic risk score to detect protective variants. After minimizing the influence of 19 common genetic risk loci on case-control status, we targeted single variants of large effect and the aggregate effect of weaker variants within genes and pathways. Single variant tests were conducted on all variants, while gene-based and pathway analyses were conducted on three subsets of data: 1) rare (≤1% MAF in the European population) stop, splice, or damaging missense variants, 2) all rare variants, and 3) all variants. All analyses controlled for the effects of age and sex.ResultsNo variant, gene, or pathway outside regions known to be associated with risk for advanced AMD reached genome-wide significance. However, we identified several variants with substantial differences in allele frequency between cases and controls with strong additive effects on affection status after controlling for age and sex. Protective effects trending toward significance were detected at two loci identified in single-variant analyses: an intronic variant in FBLN7 (the gene encoding fibulin 7) and at three variants near pyridoxal (pyridoxine, vitamin B6) kinase (PDXK). Aggregate rare-variant analyses suggested evidence for association at ASRGL1, a gene previously linked to photoreceptor cell death, and at BSDC1. In known AMD loci we also identified 29 novel or rare damaging missense or stop/splice variants in our sample of cases and controls.ConclusionsIdentified variants and genes may highlight regions important in the pathogenesis of AMD and are key targets for replication.

Dataset Information

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

Aims/hypothesis

Methods

Conclusions/interpretation

Publications

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

Similar Datasets

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