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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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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]

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