Genetic effects influencing risk for major depressive disorder in China and Europe

T. B. Bigdeli, S. Ripke, R. E. Peterson, M. Trzaskowski, S. A. Bacanu, A. Abdellaoui, T. F.M. Andlauer, A. T.F. Beekman, K. Berger, D. H.R. Blackwood, D. I. Boomsma, G. Breen, H. N. Buttenschøn, E. M. Byrne, S. Cichon, T. K. Clarke, B. Couvy-Duchesne, N. Craddock, E. J.C. De Geus, F. Degenhardt & 31 others E. C. Dunn, A. C. Edwards, A. H. Fanous, A. J. Forstner, J. Frank, M. Gill, S. D. Gordon, H. J. Grabe, S. P. Hamilton, O. Hardiman, C. Hayward, A. C. Heath, A. K. Henders, S. Herms, I. B. Hickie, P. Hoffmann, G. Homuth, J. J. Hottenga, M. Ising, R. Jansen, S. Kloiber, J. A. Knowles, M. Lang, Q. S. Li, Y. Milaneschi, B. W.J.H. Penninx, W. J. Peyrot, R. Schoevers, J. H. Smit, G. Van Grootheest, on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (∼30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor = 8.08) but failed to replicate in an independent European sample (P = 0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

Original languageEnglish
Article numbere1074
JournalTranslational Psychiatry
Volume7
Issue number3
DOIs
Publication statusPublished - 2017

Cite this

Bigdeli, T. B., Ripke, S., Peterson, R. E., Trzaskowski, M., Bacanu, S. A., Abdellaoui, A., ... on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2017). Genetic effects influencing risk for major depressive disorder in China and Europe. Translational Psychiatry, 7(3), [e1074]. https://doi.org/10.1038/tp.2016.292
Bigdeli, T. B. ; Ripke, S. ; Peterson, R. E. ; Trzaskowski, M. ; Bacanu, S. A. ; Abdellaoui, A. ; Andlauer, T. F.M. ; Beekman, A. T.F. ; Berger, K. ; Blackwood, D. H.R. ; Boomsma, D. I. ; Breen, G. ; Buttenschøn, H. N. ; Byrne, E. M. ; Cichon, S. ; Clarke, T. K. ; Couvy-Duchesne, B. ; Craddock, N. ; De Geus, E. J.C. ; Degenhardt, F. ; Dunn, E. C. ; Edwards, A. C. ; Fanous, A. H. ; Forstner, A. J. ; Frank, J. ; Gill, M. ; Gordon, S. D. ; Grabe, H. J. ; Hamilton, S. P. ; Hardiman, O. ; Hayward, C. ; Heath, A. C. ; Henders, A. K. ; Herms, S. ; Hickie, I. B. ; Hoffmann, P. ; Homuth, G. ; Hottenga, J. J. ; Ising, M. ; Jansen, R. ; Kloiber, S. ; Knowles, J. A. ; Lang, M. ; Li, Q. S. ; Milaneschi, Y. ; Penninx, B. W.J.H. ; Peyrot, W. J. ; Schoevers, R. ; Smit, J. H. ; Van Grootheest, G. ; on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. / Genetic effects influencing risk for major depressive disorder in China and Europe. In: Translational Psychiatry. 2017 ; Vol. 7, No. 3.
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title = "Genetic effects influencing risk for major depressive disorder in China and Europe",
abstract = "Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (∼30-40{\%}), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor = 8.08) but failed to replicate in an independent European sample (P = 0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.",
author = "Bigdeli, {T. B.} and S. Ripke and Peterson, {R. E.} and M. Trzaskowski and Bacanu, {S. A.} and A. Abdellaoui and Andlauer, {T. F.M.} and Beekman, {A. T.F.} and K. Berger and Blackwood, {D. H.R.} and Boomsma, {D. I.} and G. Breen and Buttensch{\o}n, {H. N.} and Byrne, {E. M.} and S. Cichon and Clarke, {T. K.} and B. Couvy-Duchesne and N. Craddock and {De Geus}, {E. J.C.} and F. Degenhardt and Dunn, {E. C.} and Edwards, {A. C.} and Fanous, {A. H.} and Forstner, {A. J.} and J. Frank and M. Gill and Gordon, {S. D.} and Grabe, {H. J.} and Hamilton, {S. P.} and O. Hardiman and C. Hayward and Heath, {A. C.} and Henders, {A. K.} and S. Herms and Hickie, {I. B.} and P. Hoffmann and G. Homuth and Hottenga, {J. J.} and M. Ising and R. Jansen and S. Kloiber and Knowles, {J. A.} and M. Lang and Li, {Q. S.} and Y. Milaneschi and Penninx, {B. W.J.H.} and Peyrot, {W. J.} and R. Schoevers and Smit, {J. H.} and {Van Grootheest}, G. and {on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium}",
year = "2017",
doi = "10.1038/tp.2016.292",
language = "English",
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journal = "Translational Psychiatry",
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Bigdeli, TB, Ripke, S, Peterson, RE, Trzaskowski, M, Bacanu, SA, Abdellaoui, A, Andlauer, TFM, Beekman, ATF, Berger, K, Blackwood, DHR, Boomsma, DI, Breen, G, Buttenschøn, HN, Byrne, EM, Cichon, S, Clarke, TK, Couvy-Duchesne, B, Craddock, N, De Geus, EJC, Degenhardt, F, Dunn, EC, Edwards, AC, Fanous, AH, Forstner, AJ, Frank, J, Gill, M, Gordon, SD, Grabe, HJ, Hamilton, SP, Hardiman, O, Hayward, C, Heath, AC, Henders, AK, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Hottenga, JJ, Ising, M, Jansen, R, Kloiber, S, Knowles, JA, Lang, M, Li, QS, Milaneschi, Y, Penninx, BWJH, Peyrot, WJ, Schoevers, R, Smit, JH, Van Grootheest, G & on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium 2017, 'Genetic effects influencing risk for major depressive disorder in China and Europe' Translational Psychiatry, vol. 7, no. 3, e1074. https://doi.org/10.1038/tp.2016.292

Genetic effects influencing risk for major depressive disorder in China and Europe. / Bigdeli, T. B.; Ripke, S.; Peterson, R. E.; Trzaskowski, M.; Bacanu, S. A.; Abdellaoui, A.; Andlauer, T. F.M.; Beekman, A. T.F.; Berger, K.; Blackwood, D. H.R.; Boomsma, D. I.; Breen, G.; Buttenschøn, H. N.; Byrne, E. M.; Cichon, S.; Clarke, T. K.; Couvy-Duchesne, B.; Craddock, N.; De Geus, E. J.C.; Degenhardt, F.; Dunn, E. C.; Edwards, A. C.; Fanous, A. H.; Forstner, A. J.; Frank, J.; Gill, M.; Gordon, S. D.; Grabe, H. J.; Hamilton, S. P.; Hardiman, O.; Hayward, C.; Heath, A. C.; Henders, A. K.; Herms, S.; Hickie, I. B.; Hoffmann, P.; Homuth, G.; Hottenga, J. J.; Ising, M.; Jansen, R.; Kloiber, S.; Knowles, J. A.; Lang, M.; Li, Q. S.; Milaneschi, Y.; Penninx, B. W.J.H.; Peyrot, W. J.; Schoevers, R.; Smit, J. H.; Van Grootheest, G.; on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

In: Translational Psychiatry, Vol. 7, No. 3, e1074, 2017.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Genetic effects influencing risk for major depressive disorder in China and Europe

AU - Bigdeli, T. B.

AU - Ripke, S.

AU - Peterson, R. E.

AU - Trzaskowski, M.

AU - Bacanu, S. A.

AU - Abdellaoui, A.

AU - Andlauer, T. F.M.

AU - Beekman, A. T.F.

AU - Berger, K.

AU - Blackwood, D. H.R.

AU - Boomsma, D. I.

AU - Breen, G.

AU - Buttenschøn, H. N.

AU - Byrne, E. M.

AU - Cichon, S.

AU - Clarke, T. K.

AU - Couvy-Duchesne, B.

AU - Craddock, N.

AU - De Geus, E. J.C.

AU - Degenhardt, F.

AU - Dunn, E. C.

AU - Edwards, A. C.

AU - Fanous, A. H.

AU - Forstner, A. J.

AU - Frank, J.

AU - Gill, M.

AU - Gordon, S. D.

AU - Grabe, H. J.

AU - Hamilton, S. P.

AU - Hardiman, O.

AU - Hayward, C.

AU - Heath, A. C.

AU - Henders, A. K.

AU - Herms, S.

AU - Hickie, I. B.

AU - Hoffmann, P.

AU - Homuth, G.

AU - Hottenga, J. J.

AU - Ising, M.

AU - Jansen, R.

AU - Kloiber, S.

AU - Knowles, J. A.

AU - Lang, M.

AU - Li, Q. S.

AU - Milaneschi, Y.

AU - Penninx, B. W.J.H.

AU - Peyrot, W. J.

AU - Schoevers, R.

AU - Smit, J. H.

AU - Van Grootheest, G.

AU - on behalf of the CONVERGE consortium and Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

PY - 2017

Y1 - 2017

N2 - Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (∼30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor = 8.08) but failed to replicate in an independent European sample (P = 0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

AB - Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (∼30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor = 8.08) but failed to replicate in an independent European sample (P = 0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

UR - http://www.scopus.com/inward/record.url?scp=85020498216&partnerID=8YFLogxK

U2 - 10.1038/tp.2016.292

DO - 10.1038/tp.2016.292

M3 - Article

VL - 7

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

IS - 3

M1 - e1074

ER -

Bigdeli TB, Ripke S, Peterson RE, Trzaskowski M, Bacanu SA, Abdellaoui A et al. Genetic effects influencing risk for major depressive disorder in China and Europe. Translational Psychiatry. 2017;7(3). e1074. https://doi.org/10.1038/tp.2016.292