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

T B Bigdeli; S Ripke; R E Peterson; Maciej 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; 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; S Lucae; D J MacIntyre; P A F Madden; N G Martin; P J McGrath; P McGuffin; A M McIntosh; S E Medland; D Mehta; C M Middeldorp; Y Milaneschi; G W Montgomery; O Mors; B Müller-Myhsok; M Nauck; D R Nyholt; M M Nöthen; M J Owen; B W J H Penninx; M L Pergadia; R H Perlis; W J Peyrot; D J Porteous; J B Potash; J P Rice; M Rietschel; B P Riley; M Rivera; R Schoevers; T G Schulze; J Shi; S I Shyn; J H Smit; J W Smoller; F Streit; J Strohmaier; A Teumer; J Treutlein; S Van der Auwera; G van Grootheest; A M van Hemert; H Völzke; B T Webb; M M Weissman; J Wellmann; G Willemsen; S H Witt; D F Levinson; C M Lewis; N R Wray; J Flint; P F Sullivan; K S Kendler

doi:10.1038/tp.2016.292

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

T B Bigdeli, S Ripke, R E Peterson, Maciej 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 DegenhardtE 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, S Lucae, D J MacIntyre, P A F Madden, N G Martin, P J McGrath, P McGuffin, A M McIntosh, S E Medland, D Mehta, C M Middeldorp, Y Milaneschi, G W Montgomery, O Mors, B Müller-Myhsok, M Nauck, D R Nyholt, M M Nöthen, M J Owen, B W J H Penninx, M L Pergadia, R H Perlis, W J Peyrot, D J Porteous, J B Potash, J P Rice, M Rietschel, B P Riley, M Rivera, R Schoevers, T G Schulze, J Shi, S I Shyn, J H Smit, J W Smoller, F Streit, J Strohmaier, A Teumer, J Treutlein, S Van der Auwera, G van Grootheest, A M van Hemert, H Völzke, B T Webb, M M Weissman, J Wellmann, G Willemsen, S H Witt, D F Levinson, C M Lewis, N R Wray, J Flint, P F Sullivan, K S Kendler

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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 language	English
Pages (from-to)	e1074
Journal	Translational psychiatry
Volume	7
Issue number	3
DOIs	https://doi.org/10.1038/tp.2016.292
Publication status	Published - 28 Mar 2017

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Genetic effects influencing risk_BIGDELI_Publishedonline28March2017_GOLD VoR (CC-BY)Final published version, 246 KBLicence: CC BY

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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., ... Kendler, K. S. (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

@article{5abd8a6f3bfe4b60876ded6534bcd79c,

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 Maciej Trzaskowski and S-A Bacanu 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 T-K Clarke 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 J-J Hottenga and M Ising and R Jansen and S Kloiber and Knowles, {J A} and M Lang and Li, {Q S} and S Lucae and MacIntyre, {D J} and Madden, {P A F} and Martin, {N G} and McGrath, {P J} and P McGuffin and McIntosh, {A M} and Medland, {S E} and D Mehta and Middeldorp, {C M} and Y Milaneschi and Montgomery, {G W} and O Mors and B M{\"u}ller-Myhsok and M Nauck and Nyholt, {D R} and N{\"o}then, {M M} and Owen, {M J} and Penninx, {B W J H} and Pergadia, {M L} and Perlis, {R H} and Peyrot, {W J} and Porteous, {D J} and Potash, {J B} and Rice, {J P} and M Rietschel and Riley, {B P} and M Rivera and R Schoevers and Schulze, {T G} and J Shi and Shyn, {S I} and Smit, {J H} and Smoller, {J W} and F Streit and J Strohmaier and A Teumer and J Treutlein and {Van der Auwera}, S and {van Grootheest}, G and {van Hemert}, {A M} and H V{\"o}lzke and Webb, {B T} and Weissman, {M M} and J Wellmann and G Willemsen and Witt, {S H} and Levinson, {D F} and Lewis, {C M} and Wray, {N R} and J Flint and Sullivan, {P F} and Kendler, {K S}",

year = "2017",

month = mar,

day = "28",

doi = "10.1038/tp.2016.292",

language = "English",

volume = "7",

pages = "e1074",

journal = "Translational psychiatry",

issn = "2158-3188",

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Bigdeli, TB, Ripke, S, Peterson, RE, Trzaskowski, M, Bacanu, S-A, Abdellaoui, A, Andlauer, TFM, Beekman, ATF, Berger, K, Blackwood, DHR, Boomsma, DI, Breen, G, Buttenschøn, HN, Byrne, EM, Cichon, S, Clarke, T-K, 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, J-J, Ising, M, Jansen, R, Kloiber, S, Knowles, JA, Lang, M, Li, QS, Lucae, S, MacIntyre, DJ, Madden, PAF , Martin, NG, McGrath, PJ, McGuffin, P, McIntosh, AM, Medland, SE, Mehta, D, Middeldorp, CM, Milaneschi, Y, Montgomery, GW, Mors, O, Müller-Myhsok, B, Nauck, M, Nyholt, DR, Nöthen, MM, Owen, MJ, Penninx, BWJH, Pergadia, ML, Perlis, RH, Peyrot, WJ, Porteous, DJ, Potash, JB, Rice, JP, Rietschel, M, Riley, BP, Rivera, M, Schoevers, R, Schulze, TG, Shi, J, Shyn, SI, Smit, JH, Smoller, JW, Streit, F, Strohmaier, J, Teumer, A, Treutlein, J, Van der Auwera, S, van Grootheest, G, van Hemert, AM, Völzke, H, Webb, BT, Weissman, MM, Wellmann, J, Willemsen, G, Witt, SH, Levinson, DF, Lewis, CM, Wray, NR, Flint, J, Sullivan, PF & Kendler, KS 2017, 'Genetic effects influencing risk for major depressive disorder in China and Europe', Translational psychiatry, vol. 7, no. 3, pp. e1074. https://doi.org/10.1038/tp.2016.292

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, Maciej

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 - Lucae, S

AU - MacIntyre, D J

AU - Madden, P A F

AU - Martin, N G

AU - McGrath, P J

AU - McGuffin, P

AU - McIntosh, A M

AU - Medland, S E

AU - Mehta, D

AU - Middeldorp, C M

AU - Milaneschi, Y

AU - Montgomery, G W

AU - Mors, O

AU - Müller-Myhsok, B

AU - Nauck, M

AU - Nyholt, D R

AU - Nöthen, M M

AU - Owen, M J

AU - Penninx, B W J H

AU - Pergadia, M L

AU - Perlis, R H

AU - Peyrot, W J

AU - Porteous, D J

AU - Potash, J B

AU - Rice, J P

AU - Rietschel, M

AU - Riley, B P

AU - Rivera, M

AU - Schoevers, R

AU - Schulze, T G

AU - Shi, J

AU - Shyn, S I

AU - Smit, J H

AU - Smoller, J W

AU - Streit, F

AU - Strohmaier, J

AU - Teumer, A

AU - Treutlein, J

AU - Van der Auwera, S

AU - van Grootheest, G

AU - van Hemert, A M

AU - Völzke, H

AU - Webb, B T

AU - Weissman, M M

AU - Wellmann, J

AU - Willemsen, G

AU - Witt, S H

AU - Levinson, D F

AU - Lewis, C M

AU - Wray, N R

AU - Flint, J

AU - Sullivan, P F

AU - Kendler, K S

PY - 2017/3/28

Y1 - 2017/3/28

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.

U2 - 10.1038/tp.2016.292

DO - 10.1038/tp.2016.292

M3 - Article

C2 - 28350396

SN - 2158-3188

VL - 7

SP - e1074

JO - Translational psychiatry

JF - Translational psychiatry

IS - 3

ER -

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

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