A genome-wide association study of depressive symptoms

Karin Hek, Ayse Demirkan, Jari Lahti, Antonio Terracciano, Alexander Teumer, Marilyn C. Cornelis, Najaf Amin, Erin Bakshis, Jens Baumert, Jingzhong Ding, Yongmei Liu, Kristin Marciante, Osorio Meirelles, Michael A. Nalls, Yan V. Sun, Nicole Vogelzangs, Lei Yu, Stefania Bandinelli, Emelia J. Benjamin, David A. BennettDorret Boomsma, Alessandra Cannas, Laura H. Coker, Eco De Geus, Philip L. De Jager, Ana V. Diez-Roux, Shaun Purcell, Frank B. Hu, Eric B. Rimm, David J. Hunter, Majken K. Jensen, Gary Curhan, Kenneth Rice, Alan D. Penman, Jerome I. Rotter, Nona Sotoodehnia, Rebecca Emeny, Johan G. Eriksson, Denis A. Evans, Luigi Ferrucci, Myriam Fornage, Vilmundur Gudnason, Albert Hofman, Thomas Illig, Sharon Kardia, Margaret Kelly-Hayes, Karestan Koenen, Peter Kraft, Maris Kuningas, Joseph M. Massaro, David Melzer, Antonella Mulas, Cornelis L. Mulder, Anna Murray, Ben A. Oostra, Aarno Palotie, Brenda Penninx, Astrid Petersmann, Luke C. Pilling, Bruce Psaty, Rajesh Rawal, Eric M. Reiman, Andrea Schulz, Joshua M. Shulman, Andrew B. Singleton, Albert V. Smith, Angelina R. Sutin, André G. Uitterlinden, Henry Völzke, Elisabeth Widen, Kristine Yaffe, Alan B. Zonderman, Francesco Cucca, Tamara Harris, Karl Heinz Ladwig, David J. Llewellyn, Katri Räikkönen, Toshiko Tanaka, Cornelia M. Van Duijn, Hans J. Grabe, Lenore J. Launer, Kathryn L. Lunetta, Thomas H. Mosley, Anne B. Newman, Henning Tiemeier*, Joanne Murabito

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

126 Citations (Scopus)

Abstract

Background: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10-5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. Results: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10-7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10-3). This 5q21 region reached genome-wide significance (p = 4.78×10-8) in the overall meta-analysis combining discovery and replication studies (n = 51,258). Conclusions: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

Original languageEnglish
Pages (from-to)667-678
Number of pages12
JournalBiological Psychiatry
Volume73
Issue number7
DOIs
Publication statusPublished - 1 Apr 2013

Bibliographical note

Funding Information:
This Cardiovascular Health Study research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and NHLBI Grants HL080295, HL075366, HL087652, and HL105756 with additional contribution from National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm . DNA handling and genotyping was supported, in part, by Clinical and Translational Science Institute Grant UL1RR033176 to the Cedars-Sinai General Clinical Research Center Genotyping core, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK063491 to the Southern California Diabetes Endocrinology Research Center, and the Governors’ Chair in Medical Genetics (JIR).

Funding Information:
The Baltimore Longitudinal Study of Aging research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging.

Funding Information:
The Health, Aging and Body Composition research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA Grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research. Center for Inherited Disease Research is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported, in part, by the Intramural Research Program of the NIH, National Institute on Aging. Dr. Yaffe is supported by NIH Grant R01 MH086498.

Funding Information:
The Atherosclerosis Risk in Communities Study research is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 and Grants R01-HL087641, R01-HL093029, and R01-HL70825; National Human Genome Research Institute contract U01-HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the Atherosclerosis Risk in Communities Study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.

Funding Information:
Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant no. 03ZIK012) and a joint Grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG. This work was also funded by the German Research Foundation (DFG: GR 1912/5-1), Federal Ministry of Education and Research Germany, the Humboldt Foundation, and the German Research Foundation.

Funding Information:
Study of Health in Pomerania: To HJG German Research Foundation; Federal Ministry of Education and Research Germany; speakers honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Wyeth, Pfizer, Boehringer Ingelheim, and Servier; and travel funds from Lundbeck, Janssen-Cilag, Eli Lilly, Novartis, AstraZeneca, and SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. To HV research grants by Sanofi-Aventis, Biotronik, the Humboldt Foundation, the Federal Ministry of Education and Research (Germany), and the German Research Foundation. All other authors reported no biomedical financial interests or potential conflicts of interest.

Funding Information:
The genotyping for the ERF study was supported by European Special Populations Research Network and the European Commission FP6 STRP Grant (018947; LSHG-CT-2006-01947). The ERF study was further supported by Grants from the Netherlands Organisation for Scientific Research, Erasmus MC, the Centre for Medical Systems Biology, and the Netherlands Brain Foundation (HersenStichting Nederland). We are grateful to all participating individuals and their relatives, general practitioners, and neurologists for their contributions and to P. Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work, and P. Snijders for his help in data collection.

Funding Information:
Helsinki Birth Cohort Study has been supported by Grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (Grant number WT098051). We thank all study participants, as well as everybody involved in the Helsinki Birth Cohort Study.

Funding Information:
The Age, Gene/Environment Susceptibility Reykjavik Study has been funded by National Institutes of Health (NIH) contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).

Funding Information:
The Monitoring of Trends and Determinants of Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, and supported by Grants from the German Federal Ministry of Education and Research. Furthermore, the research was supported within the Munich Center of Health Sciences as part of Ludwig-Maximilians-University.

Funding Information:
The Nurses’ Health Studies are supported by NIH Grants CA 65725, CA87969 (National Cancer Institute), CA49449, CA67262, CA50385, and 5UO1CA098233.

Funding Information:
Framingham Heart Study: The phenotype-genotype association analyses were supported by R01-AG29451. “This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center."

Funding Information:
The Rush Memory and Aging Project is supported by NIA Grants R01AG15819, R01AG17917, and K08AG34290 and the Translational Genomics Research Institute. The Rush Religious Orders Study is supported by NIA Grants P30AG10161, R01AG15819, R01AG30146, and K08AG34290 and the Translational Genomics Research Institute. We thank the study participants and the staff of the Rush Alzheimer's Disease Center. Joshua Shulman was additionally supported by a Career Award for Medical Scientists from Burroughs Wellcome Fund.

Funding Information:
The Multi-Ethnic Study of Atherosclerosis (MESA) SNP Health Association Resource project is conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159 through N01-HC-95169 and UL1-RR-024156. Funding for genotyping was provided by NHLBI Contract N02-HL-6-4278 and N01-HC-65226. Funding for this project was also provided by #R01 HL101161.

Funding Information:
The Erasmus Rucphen Family (ERF) research was supported through funds from The European Community's Seventh Framework Programme (FP7/2007-2013), European Network for Genetic and Genomic Epidemiology Consortium, Grant agreement HEALTH-F4-2007- 201413.

Funding Information:
The generation and management of genome-wide association study genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research Investments (number 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015), the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research project number 050-060-810. The Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (Directorate-General XII), and the Municipality of Rotterdam. Henning Tiemeier was supported by the Vidi Grant of Netherlands Organization for the Health Research and Development (2009-017.106.370). Karin Hek was supported by a Grant from BavoEuropoort. We are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters for their help in creating the genome-wide association study database, and Dr. Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. We thank Dr. Karol Estrada, Dr. Fernando Rivadeneira, Dr. Tobias A. Knoch, Anis Abuseiris, Luc V. de Zeeuw, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP and BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium für Forschung und Technology; Grants 01 AK 803 A-H, 01 IG 07015 G) for access to their grid computing resources.

Funding Information:
The SardiNIA research was supported, in part, by the Intramural Research Program of the NIH, National Institute on Aging. Funding was also provided through contract NO1-AG-1-2109 from the NIA-NIH.

Funding Information:
The Invechhiare in Chianti Study was supported as a targeted project (ICS 110.1RS97.71) by the Italian Ministry of Health, by the U.S. National Institute on Aging (Contracts N01]AG]916413, N01]AG] 821336, 263 MD 9164 13, and 263 MD 821336), and, in part, by the Intramural Research Program, National Institute on Aging, National Institutes of Health.

Other keywords

  • Center for Epidemiologic Studies Depression Scale
  • CHARGE consortium
  • depression
  • depressive symptoms
  • genetics
  • genome-wide association study
  • meta-analysis

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