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 Nørmølle 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 A F 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 I 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: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

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 Nørmølle 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 A F 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 I 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 › Academic › peer-review

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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.

Original language	English
Pages (from-to)	322-329
Number of pages	8
Journal	Biological Psychiatry
Volume	82
Issue number	5
Early online date	8 Dec 2016
DOIs	https://doi.org/10.1016/j.biopsych.2016.11.013
Publication status	Published - 1 Sept 2017

Keywords

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

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://doi.org/10.1016/j.biopsych.2016.11.013

https://research.vu.nl/ws/files/267918063/An_Analysis_of_Two_Genome_wide_Association_Meta_analyses_Identifies_a_New_Locus_for_Broad_Depression_Phenotype.pdfLicence: Article 25fa Dutch Copyright Act

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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. Advance online publication. https://doi.org/10.1016/j.biopsych.2016.11.013

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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, Journal Article, 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{\o}rm{\o}lle} and Byrne, {Enda M} and B{\o}rglum, {Anders D} and Enrique Castelao and Sven Cichon and Toni-Kim Clarke 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 Hans-J{\"o}rgen Grabe 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 Karl-Heinz Ladwig 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 Madden, {Pamela A F} 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 Shyn, {Stanley I} 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}",

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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, T-K, 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, H-J, 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, K-H, Lahti, J, Levinson, DF, Lewis, CM, Lewis, G, Li, QS, Llewellyn, DJ, Lucae, S, Lunetta, KL, MacIntyre, DJ, Madden, PAF, 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, SI, 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

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 Nørmølle

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 A F

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 I

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 - Journal Article

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 - https://doi.org/10.1016/j.biopsych.2016.11.013

DO - https://doi.org/10.1016/j.biopsych.2016.11.013

M3 - Article

C2 - 28049566

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

Cohort Studies

UN SDGs

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