An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

Nese Direk; Stephanie Williams; Jennifer A. Smith; Stephan Ripke; Tracy Air; Azmeraw T. Amare; Najaf Amin; Bernhard T. Baune; David A. Bennett; Douglas H.R. Blackwood; Dorret Boomsma; Gerome Breen; Henriette N. Buttenschøn; Enda M. Byrne; Anders D. Børglum; Enrique Castelao; Sven Cichon; Toni Kim Clarke; Marilyn C. Cornelis; Udo Dannlowski; Philip L. De Jager; Ayse Demirkan; Enrico Domenici; Cornelia M. van Duijn; Erin C. Dunn; Johan G. Eriksson; Tonu Esko; Jessica D. Faul; Luigi Ferrucci; Myriam Fornage; Eco de Geus; Michael Gill; Scott D. Gordon; Hans Jörgen Grabe; Gerard van Grootheest; Steven P. Hamilton; Catharina A. Hartman; Andrew C. Heath; Karin Hek; Albert Hofman; Georg Homuth; Carsten Horn; Jouke Jan Hottenga; Sharon L.R. Kardia; Stefan Kloiber; Karestan Koenen; Zoltán Kutalik; Karl Heinz Ladwig; Jari Lahti; Douglas F. Levinson; Cathryn M. Lewis; Glyn Lewis; Qingqin S. Li; David J. Llewellyn; Susanne Lucae; Kathryn L. Lunetta; Donald J. MacIntyre; Pamela Madden; Nicholas G. Martin; Andrew M. McIntosh; Andres Metspalu; Yuri Milaneschi; Grant W. Montgomery; Ole Mors; Thomas H. Mosley; Joanne M. Murabito; Bertram Müller-Myhsok; Markus M. Nöthen; Dale R. Nyholt; Michael C. O'Donovan; Brenda W. Penninx; Michele L. Pergadia; Roy Perlis; James B. Potash; Martin Preisig; Shaun M. Purcell; Jorge A. Quiroz; Katri Räikkönen; John P. Rice; Marcella Rietschel; Margarita Rivera; Thomas G. Schulze; Jianxin Shi; Stanley Shyn; Grant C. Sinnamon; Johannes H. Smit; Jordan W. Smoller; Harold Snieder; Toshiko Tanaka; Katherine E. Tansey; Alexander Teumer; Rudolf Uher; Daniel Umbricht; Sandra Van der Auwera; Erin B. Ware; David R. Weir; Myrna M. Weissman; Gonneke Willemsen; Jingyun Yang; Wei Zhao; Henning Tiemeier; Patrick F. Sullivan

doi:10.1016/j.biopsych.2016.11.013

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

Nese Direk, Stephanie Williams, Jennifer A. Smith, Stephan Ripke, Tracy Air, Azmeraw T. Amare, Najaf Amin, Bernhard T. Baune, David A. Bennett, Douglas H.R. Blackwood, Dorret Boomsma, Gerome Breen, Henriette N. Buttenschøn, Enda M. Byrne, Anders D. Børglum, Enrique Castelao, Sven Cichon, Toni Kim Clarke, Marilyn C. Cornelis, Udo DannlowskiPhilip L. De Jager, Ayse Demirkan, Enrico Domenici, Cornelia M. van Duijn, Erin C. Dunn, Johan G. Eriksson, Tonu Esko, Jessica D. Faul, Luigi Ferrucci, Myriam Fornage, Eco de Geus, Michael Gill, Scott D. Gordon, Hans Jörgen Grabe, Gerard van Grootheest, Steven P. Hamilton, Catharina A. Hartman, Andrew C. Heath, Karin Hek, Albert Hofman, Georg Homuth, Carsten Horn, Jouke Jan Hottenga, Sharon L.R. Kardia, Stefan Kloiber, Karestan Koenen, Zoltán Kutalik, Karl Heinz Ladwig, Jari Lahti, Douglas F. Levinson, Cathryn M. Lewis, Glyn Lewis, Qingqin S. Li, David J. Llewellyn, Susanne Lucae, Kathryn L. Lunetta, Donald J. MacIntyre, Pamela Madden, Nicholas G. Martin, Andrew M. McIntosh, Andres Metspalu, Yuri Milaneschi, Grant W. Montgomery, Ole Mors, Thomas H. Mosley, Joanne M. Murabito, Bertram Müller-Myhsok, Markus M. Nöthen, Dale R. Nyholt, Michael C. O'Donovan, Brenda W. Penninx, Michele L. Pergadia, Roy Perlis, James B. Potash, Martin Preisig, Shaun M. Purcell, Jorge A. Quiroz, Katri Räikkönen, John P. Rice, Marcella Rietschel, Margarita Rivera, Thomas G. Schulze, Jianxin Shi, Stanley Shyn, Grant C. Sinnamon, Johannes H. Smit, Jordan W. Smoller, Harold Snieder, Toshiko Tanaka, Katherine E. Tansey, Alexander Teumer, Rudolf Uher, Daniel Umbricht, Sandra Van der Auwera, Erin B. Ware, David R. Weir, Myrna M. Weissman, Gonneke Willemsen, Jingyun Yang, Wei Zhao, Henning Tiemeier, Patrick F. Sullivan

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

42 Scopus citations

Abstract

Background The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. Methods We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. Results The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10^–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p =.02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10^–9). Conclusions This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

Original language	English (US)
Pages (from-to)	322-329
Number of pages	8
Journal	Biological psychiatry
Volume	82
Issue number	5
DOIs	https://doi.org/10.1016/j.biopsych.2016.11.013
State	Published - Sep 1 2017
Externally published	Yes

Keywords

CHARGE consortium
Depressive symptoms
FHIT gene
Genome-wide association study
Major depressive disorder
Psychiatric Genomics Consortium

ASJC Scopus subject areas

Biological Psychiatry

Access to Document

10.1016/j.biopsych.2016.11.013

Cite this

Direk, N., Williams, S., Smith, J. A., Ripke, S., Air, T., Amare, A. T., Amin, N., Baune, B. T., Bennett, D. A., Blackwood, D. H. R., Boomsma, D., Breen, G., Buttenschøn, H. N., Byrne, E. M., Børglum, A. D., Castelao, E., Cichon, S., Clarke, T. K., Cornelis, M. C., ... Sullivan, P. F. (2017). An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype. Biological psychiatry, 82(5), 322-329. https://doi.org/10.1016/j.biopsych.2016.11.013

Direk, N, Williams, S, Smith, JA, Ripke, S, Air, T, Amare, AT, Amin, N, Baune, BT, Bennett, DA, Blackwood, DHR, Boomsma, D, Breen, G, Buttenschøn, HN, Byrne, EM, Børglum, AD, Castelao, E, Cichon, S, Clarke, TK, Cornelis, MC, Dannlowski, U, De Jager, PL, Demirkan, A, Domenici, E, van Duijn, CM, Dunn, EC, Eriksson, JG, Esko, T, Faul, JD, Ferrucci, L, Fornage, M, de Geus, E, Gill, M, Gordon, SD, Grabe, HJ, van Grootheest, G, Hamilton, SP, Hartman, CA, Heath, AC, Hek, K, Hofman, A, Homuth, G, Horn, C, Jan Hottenga, J, Kardia, SLR, Kloiber, S, Koenen, K, Kutalik, Z, Ladwig, KH, Lahti, J, Levinson, DF, Lewis, CM, Lewis, G, Li, QS, Llewellyn, DJ, Lucae, S, Lunetta, KL, MacIntyre, DJ, Madden, P, Martin, NG, McIntosh, AM, Metspalu, A, Milaneschi, Y, Montgomery, GW, Mors, O, Mosley, TH, Murabito, JM, Müller-Myhsok, B, Nöthen, MM, Nyholt, DR, O'Donovan, MC, Penninx, BW, Pergadia, ML, Perlis, R, Potash, JB, Preisig, M, Purcell, SM, Quiroz, JA, Räikkönen, K, Rice, JP, Rietschel, M, Rivera, M, Schulze, TG, Shi, J, Shyn, S, Sinnamon, GC, Smit, JH, Smoller, JW, Snieder, H, Tanaka, T, Tansey, KE, Teumer, A, Uher, R, Umbricht, D, Van der Auwera, S, Ware, EB, Weir, DR, Weissman, MM, Willemsen, G, Yang, J, Zhao, W, Tiemeier, H & Sullivan, PF 2017, 'An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype', Biological psychiatry, vol. 82, no. 5, pp. 322-329. https://doi.org/10.1016/j.biopsych.2016.11.013

@article{c8b763155d0f43a5911665bb12c337c9,

title = "An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype",

abstract = "Background The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. Methods We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. Results The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p =.02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10–9). Conclusions This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.",

keywords = "CHARGE consortium, Depressive symptoms, FHIT gene, Genome-wide association study, Major depressive disorder, Psychiatric Genomics Consortium",

author = "Nese Direk and Stephanie Williams and Smith, {Jennifer A.} and Stephan Ripke and Tracy Air and Amare, {Azmeraw T.} and Najaf Amin and Baune, {Bernhard T.} and Bennett, {David A.} and Blackwood, {Douglas H.R.} and Dorret Boomsma and Gerome Breen and Buttensch{\o}n, {Henriette N.} and Byrne, {Enda M.} and B{\o}rglum, {Anders D.} and Enrique Castelao and Sven Cichon and Clarke, {Toni Kim} and Cornelis, {Marilyn C.} and Udo Dannlowski and {De Jager}, {Philip L.} and Ayse Demirkan and Enrico Domenici and {van Duijn}, {Cornelia M.} and Dunn, {Erin C.} and Eriksson, {Johan G.} and Tonu Esko and Faul, {Jessica D.} and Luigi Ferrucci and Myriam Fornage and {de Geus}, Eco and Michael Gill and Gordon, {Scott D.} and Grabe, {Hans J{\"o}rgen} and {van Grootheest}, Gerard and Hamilton, {Steven P.} and Hartman, {Catharina A.} and Heath, {Andrew C.} and Karin Hek and Albert Hofman and Georg Homuth and Carsten Horn and {Jan Hottenga}, Jouke and Kardia, {Sharon L.R.} and Stefan Kloiber and Karestan Koenen and Zolt{\'a}n Kutalik and Ladwig, {Karl Heinz} and Jari Lahti and Levinson, {Douglas F.} and Lewis, {Cathryn M.} and Glyn Lewis and Li, {Qingqin S.} and Llewellyn, {David J.} and Susanne Lucae and Lunetta, {Kathryn L.} and MacIntyre, {Donald J.} and Pamela Madden and Martin, {Nicholas G.} and McIntosh, {Andrew M.} and Andres Metspalu and Yuri Milaneschi and Montgomery, {Grant W.} and Ole Mors and Mosley, {Thomas H.} and Murabito, {Joanne M.} and Bertram M{\"u}ller-Myhsok and N{\"o}then, {Markus M.} and Nyholt, {Dale R.} and O'Donovan, {Michael C.} and Penninx, {Brenda W.} and Pergadia, {Michele L.} and Roy Perlis and Potash, {James B.} and Martin Preisig and Purcell, {Shaun M.} and Quiroz, {Jorge A.} and Katri R{\"a}ikk{\"o}nen and Rice, {John P.} and Marcella Rietschel and Margarita Rivera and Schulze, {Thomas G.} and Jianxin Shi and Stanley Shyn and Sinnamon, {Grant C.} and Smit, {Johannes H.} and Smoller, {Jordan W.} and Harold Snieder and Toshiko Tanaka and Tansey, {Katherine E.} and Alexander Teumer and Rudolf Uher and Daniel Umbricht and {Van der Auwera}, Sandra and Ware, {Erin B.} and Weir, {David R.} and Weissman, {Myrna M.} and Gonneke Willemsen and Jingyun Yang and Wei Zhao and Henning Tiemeier and Sullivan, {Patrick F.}",

note = "Publisher Copyright: {\textcopyright} 2016 Society of Biological Psychiatry",

year = "2017",

month = sep,

day = "1",

doi = "10.1016/j.biopsych.2016.11.013",

language = "English (US)",

volume = "82",

pages = "322--329",

journal = "Biological psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "5",

}

TY - JOUR

T1 - An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

AU - Direk, Nese

AU - Williams, Stephanie

AU - Smith, Jennifer A.

AU - Ripke, Stephan

AU - Air, Tracy

AU - Amare, Azmeraw T.

AU - Amin, Najaf

AU - Baune, Bernhard T.

AU - Bennett, David A.

AU - Blackwood, Douglas H.R.

AU - Boomsma, Dorret

AU - Breen, Gerome

AU - Buttenschøn, Henriette N.

AU - Byrne, Enda M.

AU - Børglum, Anders D.

AU - Castelao, Enrique

AU - Cichon, Sven

AU - Clarke, Toni Kim

AU - Cornelis, Marilyn C.

AU - Dannlowski, Udo

AU - De Jager, Philip L.

AU - Demirkan, Ayse

AU - Domenici, Enrico

AU - van Duijn, Cornelia M.

AU - Dunn, Erin C.

AU - Eriksson, Johan G.

AU - Esko, Tonu

AU - Faul, Jessica D.

AU - Ferrucci, Luigi

AU - Fornage, Myriam

AU - de Geus, Eco

AU - Gill, Michael

AU - Gordon, Scott D.

AU - Grabe, Hans Jörgen

AU - van Grootheest, Gerard

AU - Hamilton, Steven P.

AU - Hartman, Catharina A.

AU - Heath, Andrew C.

AU - Hek, Karin

AU - Hofman, Albert

AU - Homuth, Georg

AU - Horn, Carsten

AU - Jan Hottenga, Jouke

AU - Kardia, Sharon L.R.

AU - Kloiber, Stefan

AU - Koenen, Karestan

AU - Kutalik, Zoltán

AU - Ladwig, Karl Heinz

AU - Lahti, Jari

AU - Levinson, Douglas F.

AU - Lewis, Cathryn M.

AU - Lewis, Glyn

AU - Li, Qingqin S.

AU - Llewellyn, David J.

AU - Lucae, Susanne

AU - Lunetta, Kathryn L.

AU - MacIntyre, Donald J.

AU - Madden, Pamela

AU - Martin, Nicholas G.

AU - McIntosh, Andrew M.

AU - Metspalu, Andres

AU - Milaneschi, Yuri

AU - Montgomery, Grant W.

AU - Mors, Ole

AU - Mosley, Thomas H.

AU - Murabito, Joanne M.

AU - Müller-Myhsok, Bertram

AU - Nöthen, Markus M.

AU - Nyholt, Dale R.

AU - O'Donovan, Michael C.

AU - Penninx, Brenda W.

AU - Pergadia, Michele L.

AU - Perlis, Roy

AU - Potash, James B.

AU - Preisig, Martin

AU - Purcell, Shaun M.

AU - Quiroz, Jorge A.

AU - Räikkönen, Katri

AU - Rice, John P.

AU - Rietschel, Marcella

AU - Rivera, Margarita

AU - Schulze, Thomas G.

AU - Shi, Jianxin

AU - Shyn, Stanley

AU - Sinnamon, Grant C.

AU - Smit, Johannes H.

AU - Smoller, Jordan W.

AU - Snieder, Harold

AU - Tanaka, Toshiko

AU - Tansey, Katherine E.

AU - Teumer, Alexander

AU - Uher, Rudolf

AU - Umbricht, Daniel

AU - Van der Auwera, Sandra

AU - Ware, Erin B.

AU - Weir, David R.

AU - Weissman, Myrna M.

AU - Willemsen, Gonneke

AU - Yang, Jingyun

AU - Zhao, Wei

AU - Tiemeier, Henning

AU - Sullivan, Patrick F.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Background The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. Methods We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. Results The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p =.02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10–9). Conclusions This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

AB - Background The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. Methods We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. Results The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p =.02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10–9). Conclusions This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

KW - CHARGE consortium

KW - Depressive symptoms

KW - FHIT gene

KW - Genome-wide association study

KW - Major depressive disorder

KW - Psychiatric Genomics Consortium

UR - http://www.scopus.com/inward/record.url?scp=85009252485&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009252485&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2016.11.013

DO - 10.1016/j.biopsych.2016.11.013

M3 - Article

C2 - 28049566

AN - SCOPUS:85009252485

SN - 0006-3223

VL - 82

SP - 322

EP - 329

JO - Biological psychiatry

JF - Biological psychiatry

IS - 5

ER -

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this