Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Russell L. McLaughlin; Dick Schijven; Wouter van Rheenen; Kristel R. van Eijk; Margaret O'Brien; René S. Kahn; Roel A. Ophoff; An Goris; Daniel G. Bradley; Ammar Al-Chalabi; Leonard H. van den Berg; Jurjen J. Luykx; Orla Hardiman; Jan H. Veldink; Project MinE GWAS Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium

doi:10.1038/ncomms14774

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Russell L. McLaughlin^*, Dick Schijven, Wouter van Rheenen, Kristel R. van Eijk, Margaret O'Brien, René S. Kahn, Roel A. Ophoff, An Goris, Daniel G. Bradley, Ammar Al-Chalabi, Leonard H. van den Berg, Jurjen J. Luykx, Orla Hardiman, Jan H. Veldink, Project MinE GWAS Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium

^*Corresponding author for this work

Macquarie University Centre for Motor Neuron Disease Research

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

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Abstract

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10^-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10^-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Original language	English
Article number	14774
Pages (from-to)	1-12
Number of pages	12
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14774
Publication status	Published - 21 Mar 2017

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10.1038/ncomms14774

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McLaughlin, R. L., Schijven, D., van Rheenen, W., van Eijk, K. R., O'Brien, M., Kahn, R. S., Ophoff, R. A., Goris, A., Bradley, D. G., Al-Chalabi, A., van den Berg, L. H., Luykx, J. J., Hardiman, O., Veldink, J. H., Project MinE GWAS Consortium, & Schizophrenia Working Group of the Psychiatric Genomics Consortium (2017). Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nature Communications, 8, 1-12. [14774]. https://doi.org/10.1038/ncomms14774

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abstract = "We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.",

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Robert} and David Cohen and Nadine Cohen and Paul Cormican and Nick Craddock and Crowley, {James J.} and David Curtis and Michael Davidson and Davis, {Kenneth L.} and Franziska Degenhardt and Favero, {Jurgen Del} and Ditte Demontis and Dimitris Dikeos and Timothy Dinan and Srdjan Djurovic and Gary Donohoe and Elodie Drapeau and Jubao Duan 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 Ina Giegling and Paola Giusti-Rodr{\'y}guez and Stephanie Godard and Goldstein, {Jacqueline I.} and Vera Golimbet and Srihari Gopal and Jacob Gratten and {De Haan}, Lieuwe and Christian Hammer and Hamshere, {Marian L.} and Mark Hansen and Thomas Hansen and Vahram Haroutunian 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 Masashi Ikeda and Inge Joa and Antonio Julia and Luba Kalaydjieva and Sena Karachanak-Yankova and Juha Karjalainen and David Kavanagh and Keller, {Matthew C.} and Kennedy, {James L.} and Andrey Khrunin and {Project MinE GWAS Consortium} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium}",

year = "2017",

month = mar,

day = "21",

doi = "10.1038/ncomms14774",

language = "English",

volume = "8",

pages = "1--12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer, Springer Nature",

}

McLaughlin, RL, Schijven, D, van Rheenen, W, van Eijk, KR, O'Brien, M, Kahn, RS, Ophoff, RA, Goris, A, Bradley, DG, Al-Chalabi, A, van den Berg, LH, Luykx, JJ, Hardiman, O, Veldink, JH, Project MinE GWAS Consortium & Schizophrenia Working Group of the Psychiatric Genomics Consortium 2017, 'Genetic correlation between amyotrophic lateral sclerosis and schizophrenia', Nature Communications, vol. 8, 14774, pp. 1-12. https://doi.org/10.1038/ncomms14774

TY - JOUR

T1 - Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

AU - McLaughlin, Russell L.

AU - Schijven, Dick

AU - van Rheenen, Wouter

AU - van Eijk, Kristel R.

AU - O'Brien, Margaret

AU - Kahn, René S.

AU - Ophoff, Roel A.

AU - Goris, An

AU - Bradley, Daniel G.

AU - Al-Chalabi, Ammar

AU - van den Berg, Leonard H.

AU - Luykx, Jurjen J.

AU - Hardiman, Orla

AU - Veldink, Jan H.

AU - Shatunov, Aleksey

AU - Dekker, Annelot M.

AU - Diekstra, Frank P.

AU - Pulit, Sara L.

AU - Van Der Spek, Rick A.A.

AU - Van Doormaal, Perry T.C.

AU - Sproviero, William

AU - Jones, Ashley R.

AU - Nicholson, Garth A.

AU - Rowe, Dominic B.

AU - Pamphlett, Roger

AU - Kiernan, Matthew C.

AU - Bauer, Denis

AU - Kahlke, Tim

AU - Williams, Kelly

AU - Eftimov, Filip

AU - Fogh, Isabella

AU - Ticozzi, Nicola

AU - Lin, Kuang

AU - Millecamps, Stephanie

AU - Salachas, Francois

AU - Meininger, Vincent

AU - Carvalho, Mamede De

AU - Pinto, Susana

AU - Mora, Jesus S.

AU - Rojas-Garcyá, Ricardo

AU - Polak, Meraida

AU - Chandran, Siddharthan

AU - Colville, Shuna

AU - Swingler, Robert

AU - Morrison, Karen E.

AU - Shaw, Pamela J.

AU - Hardy, John

AU - Orrell, Richard W.

AU - Pittman, Alan

AU - Sidle, Katie

AU - Fratta, Pietro

AU - Malaspina, Andrea

AU - Petri, Susanne

AU - Abdulla, Susanna

AU - Drepper, Carsten

AU - Sendtner, Michael

AU - Meyer, Thomas

AU - Wiedau-Pazos, Martina

AU - Lomen-Hoerth, Catherine

AU - Deerlin, Vivianna M.Van

AU - Trojanowski, John Q.

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AU - McCluskey, Leo

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AU - Wood, Nicholas

AU - Tittmann, Lukas

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AU - Franke, Andre

AU - Rietschel, Marcella

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AU - Cereda, Cristina

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AU - Comi, Giacomo P.

AU - D'Alfonso, Sandra

AU - Bertolin, Cinzia

AU - Soraru, Gianni

AU - Mazzini, Letizia

AU - Pensato, Viviana

AU - Gellera, Cinzia

AU - Tiloca, Cinzia

AU - Ratti, Antonia

AU - Calvo, Andrea

AU - Moglia, Cristina

AU - Brunetti, Maura

AU - Arcuti, Simon

AU - Capozzo, Rosa

AU - Zecca, Chiara

AU - Lunetta, Christian

AU - Penco, Silvana

AU - Riva, Nilo

AU - Padovani, Alessandro

AU - Filosto, Massimiliano

AU - Blair, Ian

AU - Nigel Leigh, P.

AU - Casale, Federico

AU - Chio, Adriano

AU - Beghi, Ettore

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AU - Albus, Margot

AU - Alexander, Madeline

AU - Amin, Farooq

AU - Bacanu, Silviu A.

AU - Begemann, Martin

AU - Belliveau, 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 - Campion, Dominique

AU - Cantor, Rita M.

AU - Carr, Vaughan J.

AU - Carrera, Noa

AU - Catts, Stanley V.

AU - Chambert, Kimberley D.

AU - Chan, Raymond C.K.

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AU - Cheung, Eric F.C.

AU - Chong, Siow Ann

AU - Cloninger, C. Robert

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AU - Cohen, Nadine

AU - Cormican, Paul

AU - Craddock, Nick

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AU - Davidson, Michael

AU - Davis, Kenneth L.

AU - Degenhardt, Franziska

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AU - Demontis, Ditte

AU - Dikeos, Dimitris

AU - Dinan, Timothy

AU - Djurovic, Srdjan

AU - Donohoe, Gary

AU - Drapeau, Elodie

AU - Duan, Jubao

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 - Giegling, Ina

AU - Giusti-Rodrýguez, Paola

AU - Godard, Stephanie

AU - Goldstein, Jacqueline I.

AU - Golimbet, Vera

AU - Gopal, Srihari

AU - Gratten, Jacob

AU - De Haan, Lieuwe

AU - Hammer, Christian

AU - Hamshere, Marian L.

AU - Hansen, Mark

AU - Hansen, Thomas

AU - Haroutunian, Vahram

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 - Joa, Inge

AU - Julia, Antonio

AU - Kalaydjieva, Luba

AU - Karachanak-Yankova, Sena

AU - Karjalainen, Juha

AU - Kavanagh, David

AU - Keller, Matthew C.

AU - Kennedy, James L.

AU - Khrunin, Andrey

AU - Project MinE GWAS Consortium

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

PY - 2017/3/21

Y1 - 2017/3/21

N2 - We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

AB - We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

UR - http://www.scopus.com/inward/record.url?scp=85016060348&partnerID=8YFLogxK

U2 - 10.1038/ncomms14774

DO - 10.1038/ncomms14774

M3 - Article

C2 - 28322246

AN - SCOPUS:85016060348

VL - 8

SP - 1

EP - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 14774

ER -

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

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