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

被引：118

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

共 70 条

[11] Building bridges across electronic health record systems through inferred phenotypic topics
Chen, You
Ghosh, Joydeep
Bejan, Cosmin Adrian
Gunter, Carl A.
Gupta, Siddharth
Kho, Abel
Liebovitz, David
Sun, Jimeng
Denny, Joshua
Malim, Bradley
[J]. JOURNAL OF BIOMEDICAL INFORMATICS, 2015, 55 : 82 - 93
[12] Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework
Cook, David
Brown, Dearg
Alexander, Robert
March, Ruth
Morgan, Paul
Satterthwaite, Gemma
Pangalos, Menelas N.
[J]. NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (06) : 419 - 431
[13] eMERGEing progress in genomics-the first seven years
Crawford, Dana C.
Crosslin, David R.
Tromp, Gerard
Kullo, Iftikhar J.
Kuivaniemi, Helena
Hayes, M. Geoffrey
Denny, Joshua C.
Bush, William S.
Haines, Jonathan L.
Roden, Dan M.
McCarty, Catherine A.
Jarvik, Gail P.
Ritchie, Marylyn D.
[J]. FRONTIERS IN GENETICS, 2014, 5
[14] A Genome-Wide Association Study of Circulating Galectin-3
de Boer, Rudolf A.
Verweij, Niek
van Veldhuisen, Dirk J.
Westra, Harm-Jan
Bakker, Stephan J. L.
Gansevoort, Ron T.
Kobold, Anneke C. Muller
van Gilst, Wiek H.
Franke, Lude
Leach, Irene Mateo
van der Harst, Pim
[J]. PLOS ONE, 2012, 7 (10):
[15] Improved whole-chromosome phasing for disease and population genetic studies
Delaneau, Olivier
Zagury, Jean-Francois
Marchini, Jonathan
[J]. NATURE METHODS, 2013, 10 (01) : 5 - 6
[16] Phenome-Wide Association Studies as a Tool to Advance Precision Medicine
Denny, Joshua C.
Bastarache, Lisa
Roden, Dan M.
[J]. ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, VOL 17, 2016, 17 : 353 - 373
[17] Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data
Denny, Joshua C.
Bastarache, Lisa
Ritchie, Marylyn D.
Carroll, Robert J.
Zink, Raquel
Mosley, Jonathan D.
Field, Julie R.
Pulley, Jill M.
Ramirez, Andrea H.
Bowton, Erica
Basford, Melissa A.
Carrell, David S.
Peissig, Peggy L.
Kho, Abel N.
Pacheco, Jennifer A.
Rasmussen, Luke V.
Crosslin, David R.
Crane, Paul K.
Pathak, Jyotishman
Bielinski, Suzette J.
Pendergrass, Sarah A.
Xu, Hua
Hindorff, Lucia A.
Li, Rongling
Manolio, Teri A.
Chute, Christopher G.
Chisholm, Rex L.
Larson, Eric B.
Jarvik, Gail P.
Brilliant, Murray H.
McCarty, Catherine A.
Kullo, Iftikhar J.
Haines, Jonathan L.
Crawford, Dana C.
Masys, Daniel R.
Roden, Dan M.
[J]. NATURE BIOTECHNOLOGY, 2013, 31 (12) : 1102 - +
[18] PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations
Denny, Joshua C.
Ritchie, Marylyn D.
Basford, Melissa A.
Pulley, Jill M.
Bastarache, Lisa
Brown-Gentry, Kristin
Wang, Deede
Masys, Dan R.
Roden, Dan M.
Crawford, Dana C.
[J]. BIOINFORMATICS, 2010, 26 (09) : 1205 - 1210
[19] Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR Study
Dewey, Frederick E.
Murray, Michael F.
Overton, John D.
Habegger, Lukas
Leader, Joseph B.
Fetterolf, Samantha N.
O'Dushlaine, Colm
Van Hout, Cristopher V.
Staples, Jeffrey
Gonzaga-Jauregui, Claudia
Metpally, Raghu
Pendergrass, Sarah A.
Giovanni, Monica A.
Kirchner, H. Lester
Balasubramanian, Suganthi
Abul-Husn, Noura S.
Hartzel, Dustin N.
Lavage, Daniel R.
Kost, Korey A.
Packer, Jonathan S.
Lopez, Alexander E.
Penn, John
Mukherjee, Semanti
Gosalia, Nehal
Kanagaraj, Manoj
Li, Alexander H.
Mitnaul, Lyndon J.
Adams, Lance J.
Person, Thomas N.
Praveen, Kavita
Marcketta, Anthony
Lebo, Matthew S.
Austin-Tse, Christina A.
Mason-Suares, Heather M.
Bruse, Shannon
Mellis, Scott
Phillips, Robert
Stahl, Neil
Murphy, Andrew
Economides, Aris
Skelding, Kimberly A.
Still, Christopher D.
Elmore, James R.
Borecki, Ingrid B.
Yancopoulos, George D.
Davis, F. Daniel
Faucett, William A.
Gottesman, Omri
Ritchie, Marylyn D.
Shuldiner, Alan R.
[J]. SCIENCE, 2016, 354 (6319)
[20] Dey R, 2017, AM J HUM GENET, V2

← 1 2 3 4 5 6 7 →