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 & 82 others 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 Bennett 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 journalArticle

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 languageEnglish (US)
JournalBiological Psychiatry
DOIs
StateAccepted/In press - Aug 3 2016
Externally publishedYes

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Depression
Phenotype
Major Depressive Disorder
Single Nucleotide Polymorphism
Genome
Chromosomes, Human, Pair 3
Linkage Disequilibrium
Genetic Polymorphisms
Sample Size
Introns
Outcome Assessment (Health Care)

Keywords

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

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Direk, N., Williams, S., Smith, J. A., Ripke, S., Air, T., Amare, A. T., ... Sullivan, P. F. (Accepted/In press). An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2016.11.013

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

In: Biological Psychiatry, 03.08.2016.

Research output: Contribution to journalArticle

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 2016, 'An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2016.11.013
Direk, Nese ; Williams, Stephanie ; Smith, Jennifer A. ; Ripke, Stephan ; Air, Tracy ; Amare, Azmeraw T. ; Amin, Najaf ; Baune, Bernhard T. ; Bennett, David A. ; Blackwood, Douglas H R ; Boomsma, Dorret ; Breen, Gerome ; Buttenschøn, Henriette N. ; Byrne, Enda M. ; Børglum, Anders D. ; Castelao, Enrique ; Cichon, Sven ; Clarke, Toni Kim ; Cornelis, Marilyn C. ; Dannlowski, Udo ; De Jager, Philip L. ; Demirkan, Ayse ; Domenici, Enrico ; van Duijn, Cornelia M. ; Dunn, Erin C. ; Eriksson, Johan G. ; Esko, Tonu ; Faul, Jessica D. ; Ferrucci, Luigi ; Fornage, Myriam ; de Geus, Eco ; Gill, Michael ; Gordon, Scott D. ; Grabe, Hans Jörgen ; van Grootheest, Gerard ; Hamilton, Steven P. ; Hartman, Catharina A. ; Heath, Andrew C. ; Hek, Karin ; Hofman, Albert ; Homuth, Georg ; Horn, Carsten ; Jan Hottenga, Jouke ; Kardia, Sharon L R ; Kloiber, Stefan ; Koenen, Karestan ; Kutalik, Zoltán ; Ladwig, Karl Heinz ; Lahti, Jari ; Levinson, Douglas F. ; Lewis, Cathryn M. ; Lewis, Glyn ; Li, Qingqin S. ; Llewellyn, David J. ; Lucae, Susanne ; Lunetta, Kathryn L. ; MacIntyre, Donald J. ; Madden, Pamela ; Martin, Nicholas G. ; McIntosh, Andrew M. ; Metspalu, Andres ; Milaneschi, Yuri ; Montgomery, Grant W. ; Mors, Ole ; Mosley, Thomas H. ; Murabito, Joanne M. ; Müller-Myhsok, Bertram ; Nöthen, Markus M. ; Nyholt, Dale R. ; O'Donovan, Michael C. ; Penninx, Brenda W. ; Pergadia, Michele L. ; Perlis, Roy ; Potash, James Bennett ; Preisig, Martin ; Purcell, Shaun M. ; Quiroz, Jorge A. ; Räikkönen, Katri ; Rice, John P. ; Rietschel, Marcella ; Rivera, Margarita ; Schulze, Thomas G. ; Shi, Jianxin ; Shyn, Stanley ; Sinnamon, Grant C. ; Smit, Johannes H. ; Smoller, Jordan W. ; Snieder, Harold ; Tanaka, Toshiko ; Tansey, Katherine E. ; Teumer, Alexander ; Uher, Rudolf ; Umbricht, Daniel ; Van der Auwera, Sandra ; Ware, Erin B. ; Weir, David R. ; Weissman, Myrna M. ; Willemsen, Gonneke ; Yang, Jingyun ; Zhao, Wei ; Tiemeier, Henning ; Sullivan, Patrick F. / An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype. In: Biological Psychiatry. 2016.
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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.",
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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 Bennett

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 - 2016/8/3

Y1 - 2016/8/3

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

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

ER -