Major depressive disorder (MDD) has at least a 5-10% lifetime population prevalence and causes severe morbidity and mortality including suicide. Heritability in twins is 0.4-0.70. Mapping of susceptibility genes may be feasible with the recurrent, early-onset subtype (MDD-RE) which demonstrates a three- to eight-fold increase in risk to first-degree relatives of probands, vs. twofold for all MDD. The complex pattern of transmission suggests multigenic transmission and/or locus heterogeneity, so that large samples may be required. We propose a four-year, six-site project to collect an estimated 770 pedigrees which contain 1,000 independent affected sibling pairs (ASPs), extended by first-degree relationships to include additional affected relatives, plus unaffected relatives (parents and sibs) for genetic phase information. All sites will have identical inclusion criteria, clinical assessment DIGS and FIGS interviews and the NEO personality inventory), interviewer training and reliability monitoring, consensus diagnostic procedures, data management system, and administrative oversight including a quality assurance program. Permanent cell line specimens will be created and DNA extracted at the NIMH-sponsored cell repository. A 10 cM genome scan will be completed on all affected subjects at the Center for Inherited Disease Research (CIDR), which has approved this project for CIDR access. A three-stage design is proposed: regions with maximum lod scores (MLS) exceeding a liberal simulation-based threshold will be identified in a genome scan of the affected individuals from the first half of the sample, and candidate regions selected which continue to meet this threshold after unaffected individuals are typed in these regions and added to the analysis. Evidence for linkage in these regions will then be tested in the entire sample with parametric and non-parametric analyses using stringent simulation-based thresholds for 5% genome-wide significance. In the four-year project period, genetic analyses can be completed on 80% of the sample (over 600 pedigrees, 800 ASPs), with the remaining families to be available by the end of the project period for immediate completion of the genome scan on these pedigrees at CIDR. A timetable is proposed for rapid sharing of all biological materials, blinded clinical data, genotypes and linkage analyses with the scientific community through the NIMH-sponsored Center for Genetic Studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH059542-03
Application #
6392429
Study Section
Special Emphasis Panel (ZRG1-MGN (01))
Program Officer
Moldin, Steven Owen
Project Start
1999-09-30
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
3
Fiscal Year
2001
Total Cost
$260,737
Indirect Cost
Name
University of Iowa
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Bigdeli, T B; Ripke, S; Peterson, R E et al. (2017) Genetic effects influencing risk for major depressive disorder in China and Europe. Transl Psychiatry 7:e1074
Power, Robert A; Tansey, Katherine E; Buttenschøn, Henriette Nørmølle et al. (2017) Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Biol Psychiatry 81:325-335
Pirooznia, M; Wang, T; Avramopoulos, D et al. (2016) High-throughput sequencing of the synaptome in major depressive disorder. Mol Psychiatry 21:650-5
Osborne, Lauren; Clive, Makena; Kimmel, Mary et al. (2016) Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels. Neuropsychopharmacology 41:1648-58
Mullins, N; Power, R A; Fisher, H L et al. (2016) Polygenic interactions with environmental adversity in the aetiology of major depressive disorder. Psychol Med 46:759-70
Boles, Richard G; Zaki, Essam A; Kerr, Jonathan R et al. (2015) Increased prevalence of two mitochondrial DNA polymorphisms in functional disease: Are we describing different parts of an energy-depleted elephant? Mitochondrion 23:1-6
Peyrot, W J; Lee, S H; Milaneschi, Y et al. (2015) The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25,000 subjects. Mol Psychiatry 20:735-43
Maier, Robert; Moser, Gerhard; Chen, Guo-Bo et al. (2015) Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder. Am J Hum Genet 96:283-94
Power, Robert A; Keller, Matthew C; Ripke, Stephan et al. (2014) A recessive genetic model and runs of homozygosity in major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 165B:157-66
Stevens, Daniel; Wilcox, Holly C; MacKinnon, Dean F et al. (2013) Posttraumatic stress disorder increases risk for suicide attempt in adults with recurrent major depression. Depress Anxiety 30:940-6

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