Phenome-wide association studies across large population cohorts support drug target validation

被引：123

作者：

Diogo, Dorothee ^{[1
]}

Tian, Chao ^{[2
]}

Franklin, Christopher S. ^{[3
]}

Alanne-Kinnunen, Mervi ^{[4
]}

March, Michael ^{[5
,6
]}

Spencer, Chris C. A. ^{[3
]}

Vangjeli, Ciara ^{[3
]}

Weale, Michael E. ^{[3
]}

Mattsson, Hannele ^{[4
,7
]}

Kilpelainen, Elina ^{[4
]}

Sleiman, Patrick M. A. ^{[5
,6
]}

Reilly, Dermot F. ^{[1
]}

McElwee, Joshua ^{[1
,16
]}

Maranville, Joseph C. ^{[1
,17
]}

Chatterjee, Arnaub K. ^{[1
,18
]}

Bhandari, Aman ^{[1
,19
]}

Nguyen, Khanh-Dung H. ^{[8
]}

Estrada, Karol ^{[8
]}

Reeve, Mary-Pat ^{[9
]}

Hutz, Janna ^{[9
]}

Bing, Nan ^{[10
]}

John, Sally ^{[8
]}

Macarthur, Daniel G. ^{[11
,12
]}

Salomaa, Veikko ^{[7
]}

Ripatti, Samuli ^{[4
,11
,13
]}

Hakonarson, Hakon ^{[5
,6
]}

Daly, Mark J. ^{[11
,12
]}

Palotie, Aarno ^{[4
,11
,12
,14
,15
]}

Hinds, David A. ^{[2
]}

Donnelly, Peter ^{[3
]}

Fox, Caroline S. ^{[1
]}

Day-Williams, Aaron G. ^{[1
,8
]}

Plenge, Robert M. ^{[1
,17
]}

Runz, Heiko ^{[1
,8
]}

机构：

[1] Merck Sharp & Dohme Ltd, Boston, MA 02115 USA

[2] 23andMe Inc, Mountain View, CA 94041 USA

[3] Genom Plc, Oxford OX1 1JD, England

[4] Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00014 Helsinki, Finland

[5] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[6] Univ Penn, Philadelphia, PA 19104 USA

[7] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland

[8] Biogen, Res & Early Dev, Cambridge, MA 02142 USA

[9] Eisai, Andover, MA 01810 USA

[10] Pfizer, Cambridge, MA 02139 USA

[11] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[12] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[13] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland

[14] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

[15] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[16] Nimbus Therapeut, Cambridge, MA 02139 USA

[17] Celgene, Cambridge, MA 02140 USA

[18] McKinsey & Co Inc, Boston, MA 02210 USA

[19] Vertex Pharmaceut, Boston, MA 02210 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

INFLAMMATORY-BOWEL-DISEASE; ELECTRONIC HEALTH RECORDS; WHOLE-GENOME ASSOCIATION; FALSE DISCOVERY RATE; BODY-MASS INDEX; GENETIC INFLUENCES; LARGE-SCALE; RISK LOCI; METAANALYSIS; EPIDEMIOLOGY;

D O I：

10.1038/s41467-018-06540-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints. Our analyses replicate 75% of known GWAS associations (P< 0.05) and identify nine study-wide significant novel associations (of 71 with FDR < 0.1). We describe associations that may predict ADEs, e.g., acne, high cholesterol, gout, and gallstones with rs738409 (p.I148M) in PNPLA3 and asthma with rs1990760 (p.T946A) in IFIH1. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery.

引用

页数：13

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