Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis

被引：306

作者：

Stahl, Eli A. ^{[1
,2
,3
]}

Wegmann, Daniel ^{[4
]}

Trynka, Gosia ^{[5
,6
]}

Gutierrez-Achury, Javier ^{[5
,6
]}

Do, Ron ^{[2
,7
,8
]}

Voight, Benjamin F. ^{[9
]}

Kraft, Peter ^{[10
]}

Chen, Robert ^{[1
,2
,3
]}

Kallberg, Henrik J. ^{[11
]}

Kurreeman, Fina A. S. ^{[1
,2
,3
]}

Kathiresan, Sekar ^{[2
,7
,8
]}

Wijmenga, Cisca ^{[5
,6
]}

Gregersen, Peter K. ^{[12
]}

Alfredsson, Lars ^{[11
]}

Siminovitch, Katherine A. ^{[13
,14
]}

Worthington, Jane ^{[15
]}

de Bakker, Paul I. W. ^{[2
,3
,16
,17
]}

Raychaudhuri, Soumya ^{[1
,2
,3
]}

Plenge, Robert M. ^{[1
,2
,3
]}

机构：

[1] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[2] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[3] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[4] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA

[5] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands

[6] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands

[7] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA

[8] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA

[9] Univ Penn, Dept Pharmacol, Perelman Sch Med, Philadelphia, PA 19104 USA

[10] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[11] Karolinska Inst Hosp Solna, Inst Environm Med, Stockholm, Sweden

[12] N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA

[13] Univ Toronto, Mt Sinai Hosp, Dept Med, Toronto, ON M5G 1X5, Canada

[14] Univ Hlth Network, Toronto, ON, Canada

[15] Univ Manchester, Arthrit Res UK Epidemiol Unit, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England

[16] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[17] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands

来源：

NATURE GENETICS | 2012年 / 44卷 / 05期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CELIAC-DISEASE; GENETIC SUSCEPTIBILITY; MISSING HERITABILITY; HEART-DISEASE; HUMAN HEIGHT; COMMON SNPS; RISK LOCI; VARIANTS;

D O I：

10.1038/ng.2232

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases.

引用

页码：483 / +

页数：9

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