LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

Brendan K Bulik-Sullivan; Po-Ru Loh; Hilary K Finucane; Stephan Ripke; Jian Yang; Nick Patterson; Mark J Daly; Alkes L Price; Benjamin M Neale; Aiden Corvin; Annette M Hartmann; Frans A Henskens; Stefan Herms; Joel N Hirschhorn; Per Hoffmann; Andrea Hofman; Mads V Hollegaard; David M Hougaard; David M Hougaard; Masashi Ikeda; James TR Walters; Inge Joa; Antonio Julia; Rene S Kahn; Luba Kalaydjieva; Sena Karachanak -Yankova; Juha Karjalainen; David Kavanagh; Matthew C Keller; Brian J Kelly; James L Kennedy; Kai-How Farh; Andrey Khrunin; Yunjung Kim; Janis Klovins; James A Knowles; Bettina Konte; Vaidutis Kucinskas; Zita Ausrele Kucinskiene; Hana Kuzelova -Ptackova; Anna K Kahler; Claudine Laurent; Peter A Holmans; Jimmy Lee Chee Keong; Phil Lee; David A Collier; Hailiang Huang; Tune H Pers; Ingrid Agartz; Esben Agerbo; Margot Albus; Madeline Alexander; Farooq Amin; Silviu Bacanu; Martin Begemann; Richard A Belliveau Jr; Judit Bene; Sarah E Bergen; Elizabeth Bevilacqua; Tim B Bigdeli; Donald W Black; Richard Bruggeman; Nancy G Buccola; Randy L Buckner; William Byerley; Wiepke Cahn; Guiqing Cai; Murray J Cairns; Dominique Campion; Rita M Cantor; Vaughan J Carr; Noa Carrera; Stanley V Catts; Kimberly D Chambert; Raymond C K Chan; Ronald Y L Chen; Eric Y H Chen; Wei Cheng; Eric F C Cheung; Siow Ann Chong; C Robert Cloninger; David Cohen; Nadine Cohen; Paul Cormican; Nick Craddock; Benedicto Crespo- Facorro; James J Crowley; David Curtis; Michael Davidson; Kenneth L Davis; Franziska Degenhardt; Jurgen D Favero; Lynn E DeLisi; Ditte Demontis; Dimitris Dikeos; Timothy Dinan; Srdjan Djurovic; Gary Donohoe; Elodie Drapeau; Jubao Duan; Alkes L Price; Frank Dudbridge; Naser Durmishi; Peter Eichhammer; Johan Eriksson; Valentina Escott-Price; Laurent Essioux; Ayman H Fanous; Martilias S Farrell; Josef Frank; Lude Franke; Robert Freedman; Nelson B Freimer; Marion Friedl; Joseph I Friedman; Menachem Fromer; Giulio Genovese; Lyudmila Georgieva; Elliot S Gershon; Ina Giegling; Paola Giusti -Rodriguez; Sang Hong Lee; Stephanie Godard; Jacqueline I Goldstein; Vera Golimbet; Srihari Gopal; Jacob Gratten; Lieuwe de Haan; Christian Hammer; Marian L Hamshere; Thomas Hansen; Vahram Haroutunian

doi:10.1038/ng.3211

LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

Brendan K Bulik-Sullivan
, Po-Ru Loh
, Hilary K Finucane
, Stephan Ripke
, Jian Yang
, Nick Patterson
, Mark J Daly
, Alkes L Price
, Benjamin M Neale
, Aiden Corvin
, Annette M Hartmann
, Frans A Henskens
, Stefan Herms
, Joel N Hirschhorn
, Per Hoffmann
, Andrea Hofman
, Mads V Hollegaard
, David M Hougaard
, David M Hougaard
, Masashi Ikeda

James TR Walters, Inge Joa, Antonio Julia, Rene S Kahn, Luba Kalaydjieva, Sena Karachanak -Yankova, Juha Karjalainen, David Kavanagh, Matthew C Keller, Brian J Kelly, James L Kennedy, Kai-How Farh, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova -Ptackova, Anna K Kahler, Claudine Laurent, Peter A Holmans, Jimmy Lee Chee Keong, Phil Lee, David A Collier, Hailiang Huang, Tune H Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu Bacanu, Martin Begemann, Richard A Belliveau Jr, Judit Bene, Sarah E Bergen, Elizabeth Bevilacqua, Tim B Bigdeli, Donald W Black, Richard Bruggeman, Nancy G Buccola, Randy L Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Murray J Cairns, Dominique Campion, Rita M Cantor, Vaughan J Carr, Noa Carrera, Stanley V Catts, Kimberly D Chambert, Raymond C K Chan, Ronald Y L Chen, Eric Y H Chen, Wei Cheng, Eric F C Cheung, Siow Ann Chong, C Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, Benedicto Crespo- Facorro, James J Crowley, David Curtis, Michael Davidson, Kenneth L Davis, Franziska Degenhardt, Jurgen D Favero, Lynn E DeLisi, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Alkes L Price, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H Fanous, Martilias S Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B Freimer, Marion Friedl, Joseph I Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Elliot S Gershon, Ina Giegling, Paola Giusti -Rodriguez, Sang Hong Lee, Stephanie Godard, Jacqueline I Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L Hamshere, Thomas Hansen, Vahram Haroutunian

School of Environmental & Rural Science

Research output: Contribution to journal › Article › peer-review

4134 Citations (Scopus)

Abstract

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

Original language	English
Pages (from-to)	291-295
Journal	Nature Genetics
Volume	47
Issue number	3
DOIs	https://doi.org/10.1038/ng.3211
Publication status	Published - 2015

Keywords

Gene Expression (incl. Microarray and other genome-wide approaches)

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Bulik-Sullivan, B. K., Loh, P.-R., Finucane, H. K., Ripke, S., Yang, J., Patterson, N., Daly, M. J., Price, A. L., Neale, B. M., Corvin, A., Hartmann, A. M., Henskens, F. A., Herms, S., Hirschhorn, J. N., Hoffmann, P., Hofman, A., Hollegaard, M. V., Hougaard, D. M., Hougaard, D. M., ... Haroutunian, V. (2015). LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nature Genetics, 47(3), 291-295. https://doi.org/10.1038/ng.3211

@article{16295832204d47f1a8471bb98cc08fab,

title = "LD Score regression distinguishes confounding from polygenicity in genome-wide association studies",

abstract = "Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.",

keywords = "Gene Expression (incl. Microarray and other genome-wide approaches)",

author = "Bulik-Sullivan, \{Brendan K\} and Po-Ru Loh and Finucane, \{Hilary K\} and Stephan Ripke and Jian Yang and Nick Patterson and Daly, \{Mark J\} and Price, \{Alkes L\} and Neale, \{Benjamin M\} and Aiden Corvin and Hartmann, \{Annette M\} and Henskens, \{Frans A\} and Stefan Herms and Hirschhorn, \{Joel N\} and Per Hoffmann and Andrea Hofman and Hollegaard, \{Mads V\} and Hougaard, \{David M\} and Hougaard, \{David M\} and Masashi Ikeda and Walters, \{James TR\} and Inge Joa and Antonio Julia and Kahn, \{Rene S\} and Luba Kalaydjieva and \{Karachanak -Yankova\}, Sena and Juha Karjalainen and David Kavanagh and Keller, \{Matthew C\} and Kelly, \{Brian J\} and Kennedy, \{James L\} and Kai-How Farh and Andrey Khrunin and Yunjung Kim and Janis Klovins and Knowles, \{James A\} and Bettina Konte and Vaidutis Kucinskas and Kucinskiene, \{Zita Ausrele\} and \{Kuzelova -Ptackova\}, Hana and Kahler, \{Anna K\} and Claudine Laurent and Holmans, \{Peter A\} and \{Lee Chee Keong\}, Jimmy and Phil Lee and Collier, \{David A\} and Hailiang Huang and Pers, \{Tune H\} and Ingrid Agartz and Esben Agerbo and Margot Albus and Madeline Alexander and Farooq Amin and Silviu Bacanu and Martin Begemann and \{Belliveau Jr\}, \{Richard A\} and Judit Bene and Bergen, \{Sarah E\} and Elizabeth Bevilacqua and Bigdeli, \{Tim B\} and Black, \{Donald W\} and Richard Bruggeman and Buccola, \{Nancy G\} and Buckner, \{Randy L\} and William Byerley and Wiepke Cahn and Guiqing Cai and Cairns, \{Murray J\} and Dominique Campion and Cantor, \{Rita M\} and Carr, \{Vaughan J\} and Noa Carrera and Catts, \{Stanley V\} and Chambert, \{Kimberly D\} and Chan, \{Raymond C K\} and Chen, \{Ronald Y L\} and Chen, \{Eric Y H\} and Wei Cheng and Cheung, \{Eric F C\} and Chong, \{Siow Ann\} and Cloninger, \{C Robert\} and David Cohen and Nadine Cohen and Paul Cormican and Nick Craddock and \{Crespo- Facorro\}, Benedicto and Crowley, \{James J\} and David Curtis and Michael Davidson and Davis, \{Kenneth L\} and Franziska Degenhardt and Favero, \{Jurgen D\} and DeLisi, \{Lynn E\} and Ditte Demontis and Dimitris Dikeos and Timothy Dinan and Srdjan Djurovic and Gary Donohoe and Elodie Drapeau and Jubao Duan and Price, \{Alkes L\} and Frank Dudbridge and Naser Durmishi and Peter Eichhammer and Johan Eriksson and Valentina Escott-Price and Laurent Essioux and Fanous, \{Ayman H\} and Farrell, \{Martilias S\} and Josef Frank and Lude Franke and Robert Freedman and Freimer, \{Nelson B\} and Marion Friedl and Friedman, \{Joseph I\} and Menachem Fromer and Giulio Genovese and Lyudmila Georgieva and Gershon, \{Elliot S\} and Ina Giegling and \{Giusti -Rodriguez\}, Paola and Lee, \{Sang Hong\} and Stephanie Godard and Goldstein, \{Jacqueline I\} and Vera Golimbet and Srihari Gopal and Jacob Gratten and Haan, \{Lieuwe de\} and Christian Hammer and Hamshere, \{Marian L\} and Thomas Hansen and Vahram Haroutunian",

year = "2015",

doi = "10.1038/ng.3211",

language = "English",

volume = "47",

pages = "291--295",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

}

Bulik-Sullivan, BK, Loh, P-R, Finucane, HK, Ripke, S, Yang, J, Patterson, N, Daly, MJ, Price, AL, Neale, BM, Corvin, A, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Hougaard, DM, Ikeda, M, Walters, JTR, Joa, I, Julia, A, Kahn, RS, Kalaydjieva, L, Karachanak -Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kelly, BJ, Kennedy, JL, Farh, K-H, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova -Ptackova, H, Kahler, AK, Laurent, C, Holmans, PA, Lee Chee Keong, J, Lee, P, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, S, Begemann, M, Belliveau Jr, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crespo- Facorro, B, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Favero, JD, DeLisi, LE, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Price, AL, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Gershon, ES, Giegling, I, Giusti -Rodriguez, P, Lee, SH, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, Haan, LD, Hammer, C, Hamshere, ML, Hansen, T & Haroutunian, V 2015, 'LD Score regression distinguishes confounding from polygenicity in genome-wide association studies', Nature Genetics, vol. 47, no. 3, pp. 291-295. https://doi.org/10.1038/ng.3211

TY - JOUR

T1 - LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

AU - Bulik-Sullivan, Brendan K

AU - Loh, Po-Ru

AU - Finucane, Hilary K

AU - Ripke, Stephan

AU - Yang, Jian

AU - Patterson, Nick

AU - Daly, Mark J

AU - Price, Alkes L

AU - Neale, Benjamin M

AU - Corvin, Aiden

AU - Hartmann, Annette M

AU - Henskens, Frans A

AU - Herms, Stefan

AU - Hirschhorn, Joel N

AU - Hoffmann, Per

AU - Hofman, Andrea

AU - Hollegaard, Mads V

AU - Hougaard, David M

AU - Ikeda, Masashi

AU - Walters, James TR

AU - Joa, Inge

AU - Julia, Antonio

AU - Kahn, Rene S

AU - Kalaydjieva, Luba

AU - Karachanak -Yankova, Sena

AU - Karjalainen, Juha

AU - Kavanagh, David

AU - Keller, Matthew C

AU - Kelly, Brian J

AU - Kennedy, James L

AU - Farh, Kai-How

AU - Khrunin, Andrey

AU - Kim, Yunjung

AU - Klovins, Janis

AU - Knowles, James A

AU - Konte, Bettina

AU - Kucinskas, Vaidutis

AU - Kucinskiene, Zita Ausrele

AU - Kuzelova -Ptackova, Hana

AU - Kahler, Anna K

AU - Laurent, Claudine

AU - Holmans, Peter A

AU - Lee Chee Keong, Jimmy

AU - Lee, Phil

AU - Collier, David A

AU - Huang, Hailiang

AU - Pers, Tune H

AU - Agartz, Ingrid

AU - Agerbo, Esben

AU - Albus, Margot

AU - Alexander, Madeline

AU - Amin, Farooq

AU - Bacanu, Silviu

AU - Begemann, Martin

AU - Belliveau Jr, Richard A

AU - Bene, Judit

AU - Bergen, Sarah E

AU - Bevilacqua, Elizabeth

AU - Bigdeli, Tim B

AU - Black, Donald W

AU - Bruggeman, Richard

AU - Buccola, Nancy G

AU - Buckner, Randy L

AU - Byerley, William

AU - Cahn, Wiepke

AU - Cai, Guiqing

AU - Cairns, Murray J

AU - Campion, Dominique

AU - Cantor, Rita M

AU - Carr, Vaughan J

AU - Carrera, Noa

AU - Catts, Stanley V

AU - Chambert, Kimberly D

AU - Chan, Raymond C K

AU - Chen, Ronald Y L

AU - Chen, Eric Y H

AU - Cheng, Wei

AU - Cheung, Eric F C

AU - Chong, Siow Ann

AU - Cloninger, C Robert

AU - Cohen, David

AU - Cohen, Nadine

AU - Cormican, Paul

AU - Craddock, Nick

AU - Crespo- Facorro, Benedicto

AU - Crowley, James J

AU - Curtis, David

AU - Davidson, Michael

AU - Davis, Kenneth L

AU - Degenhardt, Franziska

AU - Favero, Jurgen D

AU - DeLisi, Lynn E

AU - Demontis, Ditte

AU - Dikeos, Dimitris

AU - Dinan, Timothy

AU - Djurovic, Srdjan

AU - Donohoe, Gary

AU - Drapeau, Elodie

AU - Duan, Jubao

AU - Price, Alkes L

AU - Dudbridge, Frank

AU - Durmishi, Naser

AU - Eichhammer, Peter

AU - Eriksson, Johan

AU - Escott-Price, Valentina

AU - Essioux, Laurent

AU - Fanous, Ayman H

AU - Farrell, Martilias S

AU - Frank, Josef

AU - Franke, Lude

AU - Freedman, Robert

AU - Freimer, Nelson B

AU - Friedl, Marion

AU - Friedman, Joseph I

AU - Fromer, Menachem

AU - Genovese, Giulio

AU - Georgieva, Lyudmila

AU - Gershon, Elliot S

AU - Giegling, Ina

AU - Giusti -Rodriguez, Paola

AU - Lee, Sang Hong

AU - Godard, Stephanie

AU - Goldstein, Jacqueline I

AU - Golimbet, Vera

AU - Gopal, Srihari

AU - Gratten, Jacob

AU - Haan, Lieuwe de

AU - Hammer, Christian

AU - Hamshere, Marian L

AU - Hansen, Thomas

AU - Haroutunian, Vahram

PY - 2015

Y1 - 2015

N2 - Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

AB - Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

KW - Gene Expression (incl. Microarray and other genome-wide approaches)

U2 - 10.1038/ng.3211

DO - 10.1038/ng.3211

M3 - Article

SN - 1061-4036

VL - 47

SP - 291

EP - 295

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

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