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, Buttenschon, Henriette N., Byrne, Enda M., Borglum, 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., Muller-Myhsok, Bertram, Nothen, Markus M., Nyholt, Dale R., O'Donovan, Michael C., Penninx, Brenda W., Pergadia, Michele L., Perlis, Roy, Potash, James B., Preisig, Martin, Purcell, Shaun M., Quiroz, Jorge A., Raikkonen, 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 and Sullivan, Patrick F. (2016) An analysis of two genome-wide association meta-analyses identifies a new locus for broad depression phenotype. Biological Psychiatry, 82 5: 322-329. doi:10.1016/j.biopsych.2016.11.013

Author 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
Buttenschon, Henriette N.
Byrne, Enda M.
Borglum, 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.
Muller-Myhsok, Bertram
Nothen, Markus M.
Nyholt, Dale R.
O'Donovan, Michael C.
Penninx, Brenda W.
Pergadia, Michele L.
Perlis, Roy
Potash, James B.
Preisig, Martin
Purcell, Shaun M.
Quiroz, Jorge A.
Raikkonen, 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.
Title An analysis of two genome-wide association meta-analyses identifies a new locus for broad depression phenotype
Journal name Biological Psychiatry   Check publisher's open access policy
ISSN 1873-2402
Publication date 2016-08-01
Sub-type Article (original research)
DOI 10.1016/j.biopsych.2016.11.013
Open Access Status Not yet assessed
Volume 82
Issue 5
Start page 322
End page 329
Total pages 8
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Formatted 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.
Keyword CHARGE consortium
Depressive symptoms
FHIT gene
Genome-wide association study
Major depressive disorder
Psychiatric Genomics Consortium
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
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