Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
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DOI：
10.1371/journal.pgen.1003500
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发表时间：
2013-06
期刊：
影响因子：
4.5
通讯作者：
Heid IM
中科院分区：
文献类型：
--
作者：
Randall JC;Winkler TW;Kutalik Z;Berndt SI;Jackson AU;Monda KL;Kilpeläinen TO;Esko T;Mägi R;Li S;Workalemahu T;Feitosa MF;Croteau-Chonka DC;Day FR;Fall T;Ferreira T;Gustafsson S;Locke AE;Mathieson I;Scherag A;Vedantam S;Wood AR;Liang L;Steinthorsdottir V;Thorleifsson G;Dermitzakis ET;Dimas AS;Karpe F;Min JL;Nicholson G;Clegg DJ;Person T;Krohn JP;Bauer S;Buechler C;Eisinger K;DIAGRAM Consortium;Bonnefond A;Froguel P;MAGIC Investigators;Hottenga JJ;Prokopenko I;Waite LL;Harris TB;Smith AV;Shuldiner AR;McArdle WL;Caulfield MJ;Munroe PB;Grönberg H;Chen YD;Li G;Beckmann JS;Johnson T;Thorsteinsdottir U;Teder-Laving M;Khaw KT;Wareham NJ;Zhao JH;Amin N;Oostra BA;Kraja AT;Province MA;Cupples LA;Heard-Costa NL;Kaprio J;Ripatti S;Surakka I;Collins FS;Saramies J;Tuomilehto J;Jula A;Salomaa V;Erdmann J;Hengstenberg C;Loley C;Schunkert H;Lamina C;Wichmann HE;Albrecht E;Gieger C;Hicks AA;Johansson A;Pramstaller PP;Kathiresan S;Speliotes EK;Penninx B;Hartikainen AL;Jarvelin MR;Gyllensten U;Boomsma DI;Campbell H;Wilson JF;Chanock SJ;Farrall M;Goel A;Medina-Gomez C;Rivadeneira F;Estrada K;Uitterlinden AG;Hofman A;Zillikens MC;den Heijer M;Kiemeney LA;Maschio A;Hall P;Tyrer J;Teumer A;Völzke H;Kovacs P;Tönjes A;Mangino M;Spector TD;Hayward C;Rudan I;Hall AS;Samani NJ;Attwood AP;Sambrook JG;Hung J;Palmer LJ;Lokki ML;Sinisalo J;Boucher G;Huikuri H;Lorentzon M;Ohlsson C;Eklund N;Eriksson JG;Barlassina C;Rivolta C;Nolte IM;Snieder H;Van der Klauw MM;Van Vliet-Ostaptchouk JV;Gejman PV;Shi J;Jacobs KB;Wang Z;Bakker SJ;Mateo Leach I;Navis G;van der Harst P;Martin NG;Medland SE;Montgomery GW;Yang J;Chasman DI;Ridker PM;Rose LM;Lehtimäki T;Raitakari O;Absher D;Iribarren C;Basart H;Hovingh KG;Hyppönen E;Power C;Anderson D;Beilby JP;Hui J;Jolley J;Sager H;Bornstein SR;Schwarz PE;Kristiansson K;Perola M;Lindström J;Swift AJ;Uusitupa M;Atalay M;Lakka TA;Rauramaa R;Bolton JL;Fowkes G;Fraser RM;Price JF;Fischer K;Krjutå Kov K;Metspalu A;Mihailov E;Langenberg C;Luan J;Ong KK;Chines PS;Keinanen-Kiukaanniemi SM;Saaristo TE;Edkins S;Franks PW;Hallmans G;Shungin D;Morris AD;Palmer CN;Erbel R;Moebus S;Nöthen MM;Pechlivanis S;Hveem K;Narisu N;Hamsten A;Humphries SE;Strawbridge RJ;Tremoli E;Grallert H;Thorand B;Illig T;Koenig W;Müller-Nurasyid M;Peters A;Boehm BO;Kleber ME;März W;Winkelmann BR;Kuusisto J;Laakso M;Arveiler D;Cesana G;Kuulasmaa K;Virtamo J;Yarnell JW;Kuh D;Wong A;Lind L;de Faire U;Gigante B;Magnusson PK;Pedersen NL;Dedoussis G;Dimitriou M;Kolovou G;Kanoni S;Stirrups K;Bonnycastle LL;Njølstad I;Wilsgaard T;Ganna A;Rehnberg E;Hingorani A;Kivimaki M;Kumari M;Assimes TL;Barroso I;Boehnke M;Borecki IB;Deloukas P;Fox CS;Frayling T;Groop LC;Haritunians T;Hunter D;Ingelsson E;Kaplan R;Mohlke KL;O'Connell JR;Schlessinger D;Strachan DP;Stefansson K;van Duijn CM;Abecasis GR;McCarthy MI;Hirschhorn JN;Qi L;Loos RJ;Lindgren CM;North KE;Heid IM
考虑到男性和女性之间的人体测量学差异以及先前关于遗传效应性别差异的证据，我们进行了全基因组搜索，以寻找与身高、体重、体重指数、腰围、臀围和腰臀比有关的性二态关系（133，723人），并在总共94项研究中将348个SNP纳入随访（额外的137，052人）。7个位点显示出显著的性别差异（FDR<5%），包括4个先前建立的位点（靠近GRB 14/COBLL 1、LYPLAL 1/SLC 30 A10、VEGFA、ADAMTS 9）和3个新的人体测量性状位点（靠近MAP 3 K1、HSD 17 B4、PPARG），这些位点在女性中均具有全基因组显著性（P<5×10−8），但在男性中不具有显著性。性别差异仅在腰围表型上明显，而在身高、体重、BMI或臀围上不明显。此外，我们没有发现任何证据表明男性和女性的遗传效应方向相反。PPARG基因座由于其在糖尿病遗传学和治疗中的作用而受到特别关注。我们的研究结果表明，性别特异性GWAS的价值，解开复杂性状的性二态遗传基础。男性和女性在身高、体重和身体脂肪方面存在很大差异。有趣的是，以前的工作检测腰臀比的遗传效应，以评估身体脂肪分布，发现其中许多表现出性别差异。然而，系统的搜索性别差异的遗传效应尚未进行。因此，我们在一项大型荟萃分析中对人体测量特征的性二态遗传效应进行了全基因组搜索，包括133，723名个体，并在另外137，052名个体中跟踪了有希望的变体，包括总共94项研究。结果发现7个具有显著性别差异的基因座，包括4个已建立的基因座（靠近GRB 14/COBLL 1、LYPLAL 1/SLC 30 A10、VEGFA、ADAMTS 9）和3个新的人体测量性状基因座（靠近MAP 3 K1、HSD 17 B4、PPARG），这些基因座在女性中均显著，而在男性中不显著。有趣的是，性别差异只观察到腰围表型，但没有身高或体重指数。我们没有发现证据表明性别差异对男性和女性具有相反的影响方向。PPARG基因座由于其与糖尿病遗传学和治疗的联系而特别感兴趣。我们的研究结果表明调查性别差异的重要性，这可能会导致更好地了解疾病机制与治疗方案的潜在相关性。
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10−8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits. Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
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