GENETICS OF EARLY-ONSET MAJOR DEPRESSION

Summary

Principal Investigator: MYRNA M contact WEISSMAN
Abstract: This is a second revision of a collaborative R01 four-year competing continuation proposal to create a large repository-based sample of cases with recurrent, early-onset major depressive disorder (MDD-RE), and to use positional cloning to identify depression susceptibility genes in regions of significant linkage in our genome scan. The completed four-year project collected 680 families containing 927 affected sibling pairs (ASPs) (MDD-RE diagnostic model) and additional affected relatives (GenRED I). Blinded clinical data and blood specimens for cell culture were deposited in the NIMH repository and are being made public. Linkage fine-mapping has demonstrated genome-wide significant linkage on chromosome 15q; in the 10 cM genome scan, suggestive sex-specific linkage was observed in three regions (6p-q, 8p, 17p), with the result on chromosome 17p approaching genome-wide significance. Six collaborating sites now propose to: (1) Collect (during Years 1-3) an additional 1,350 European-ancestry (EUR) MDD-RE probands (GenRED II) meeting identical criteria (including evidence of having an affected sibling) to create a total repository sample of 2,000 EUR MDD-RE cases, plus cell lines/DMA from available parents, unaffected sibs and male-male ASPs. (2) Initiate a repository-based collection of African-American (AA) MDD-RE probands meeting the same clinical criteria. We will collect 750 AA probands plus available parents and affected siblings, with involvement of young minority co-investigators; AA controls will be available from the repository. A site at Howard University has been added to lead this effort. AA recruitment will continue through Year 4 to build the repository sample. (3) Collect data on childhood abuse and neglect and parental loss, major environmental MOD risk factors; (4) Carry out linkage fine-mapping studies of chromosomes 17p, 1q, 5q, 6p-q, 8p and 18q to maximize evidence for linkage and to narrow candidate regions. (5) Carry out linkage disequilibrium (LD) mapping and intensive gene analysis studies in the 15q candidate region and one additional region in 2,000 EUR cases and 2,000 screened, ethnically-matched controls; and carry out LD fine-mapping studies in the most significant genes in 600 AA cases (the N available early in Year 4) and 1,000 controls, using high-throughput SNP genotyping methods, to identify a depression susceptibility gene. The proposed studies will contribute to the understanding of this devastating common disorder by identifying susceptibility genes, and by creating a public collection of biological materials and clinical data, as well as over 13 million SNP genotypes, to facilitate further investigation of recurrent MOD and related phenotypes.
Funding Period: 1999-09-30 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Is perinatal depression familial?
    Kathleen Murphy-Eberenz
    Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 3309, USA
    J Affect Disord 90:49-55. 2006
  2. ncbi Maternal inheritance in recurrent early-onset depression
    Eric R Bergemann
    Division of Medical Genetics, Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California 90027, USA
    Psychiatr Genet 20:31-4. 2010
  3. pmc The stability of parental bonding reports: a 20-year follow-up
    Eleanor Murphy
    Department of Psychiatry, College of Physicians and Surgeons, Columbia University and Division of Epidemiology, New York State Psychiatric Institute, United States
    J Affect Disord 125:307-15. 2010
  4. pmc Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans
    David T Dao
    Department of Psychiatry, University of Maryland School of Medicine, Baltimore, 21201, USA
    Biol Psychiatry 68:801-10. 2010
  5. pmc Co-morbid anxiety disorders in bipolar disorder and major depression: familial aggregation and clinical characteristics of co-morbid panic disorder, social phobia, specific phobia and obsessive-compulsive disorder
    F S Goes
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
    Psychol Med 42:1449-59. 2012
  6. pmc Association study of serotonin pathway genes in attempted suicide
    Jennifer T Judy
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
    Am J Med Genet B Neuropsychiatr Genet 159:112-9. 2012
  7. pmc A mega-analysis of genome-wide association studies for major depressive disorder
    Stephan Ripke
    Harvard University Broad Institute, USA
    Mol Psychiatry 18:497-511. 2013
  8. pmc Designing case-control studies: decisions about the controls
    Susan E Hodge
    Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
    Am J Psychiatry 169:785-9. 2012
  9. pmc Posttraumatic stress disorder increases risk for suicide attempt in adults with recurrent major depression
    Daniel Stevens
    Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Depress Anxiety 30:940-6. 2013
  10. pmc Genome-wide linkage and follow-up association study of postpartum mood symptoms
    Pamela Belmonte Mahon
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA
    Am J Psychiatry 166:1229-37. 2009

Detail Information

Publications21

  1. ncbi Is perinatal depression familial?
    Kathleen Murphy-Eberenz
    Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 3309, USA
    J Affect Disord 90:49-55. 2006
    ....
  2. ncbi Maternal inheritance in recurrent early-onset depression
    Eric R Bergemann
    Division of Medical Genetics, Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California 90027, USA
    Psychiatr Genet 20:31-4. 2010
    ..Thus, our data strengthen the hypothesis that energy metabolism may be involved in the pathogenesis of depression...
  3. pmc The stability of parental bonding reports: a 20-year follow-up
    Eleanor Murphy
    Department of Psychiatry, College of Physicians and Surgeons, Columbia University and Division of Epidemiology, New York State Psychiatric Institute, United States
    J Affect Disord 125:307-15. 2010
    ..The rarity of longitudinal research with follow-up periods exceeding 10 years creates a need for additional studies...
  4. pmc Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans
    David T Dao
    Department of Psychiatry, University of Maryland School of Medicine, Baltimore, 21201, USA
    Biol Psychiatry 68:801-10. 2010
    ..Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, with a bipolar disorder and depression diagnosis...
  5. pmc Co-morbid anxiety disorders in bipolar disorder and major depression: familial aggregation and clinical characteristics of co-morbid panic disorder, social phobia, specific phobia and obsessive-compulsive disorder
    F S Goes
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
    Psychol Med 42:1449-59. 2012
    ..This study investigates clinical correlates and familiality of four anxiety disorders in a large sample of bipolar disorder (BP) and major depressive disorder (MDD) pedigrees...
  6. pmc Association study of serotonin pathway genes in attempted suicide
    Jennifer T Judy
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
    Am J Med Genet B Neuropsychiatr Genet 159:112-9. 2012
    ..Additional studies, including assessment in larger sample sets and deep resequencing to identify rare causal variants, may be required to fully understand the role that the serotonin pathway plays in suicidal behavior...
  7. pmc A mega-analysis of genome-wide association studies for major depressive disorder
    Stephan Ripke
    Harvard University Broad Institute, USA
    Mol Psychiatry 18:497-511. 2013
    ..The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status...
  8. pmc Designing case-control studies: decisions about the controls
    Susan E Hodge
    Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
    Am J Psychiatry 169:785-9. 2012
    ..The formulas provided by the authors enable investigators to make rational decisions about removing misclassified controls or leaving them in...
  9. pmc Posttraumatic stress disorder increases risk for suicide attempt in adults with recurrent major depression
    Daniel Stevens
    Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Depress Anxiety 30:940-6. 2013
    ..We tested the hypothesis that PTSD resulting from assaultive trauma increases risk for attempted suicide among individuals with recurrent MDD...
  10. pmc Genome-wide linkage and follow-up association study of postpartum mood symptoms
    Pamela Belmonte Mahon
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA
    Am J Psychiatry 166:1229-37. 2009
    ..The authors then fine-mapped their best linkage regions, assessing single nucleotide polymorphisms (SNPs) for genetic association with postpartum symptoms...
  11. pmc An exploration of attitudes among black Americans towards psychiatric genetic research
    Eleanor Murphy
    New York State Psychiatric Institute, Division of Epidemiology in Psychiatry, Columbia University College of Physicians and Surgeons, Department of Psychiatry, USA
    Psychiatry 72:177-94. 2009
    ..Further, there is critical need to engage communities with education about genetics and mental illness, and provide opportunities for continued discussion about concerns related to genetic research...
  12. pmc Racial and ethnic differences in willingness to participate in psychiatric genetic research
    Eleanor J Murphy
    Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York 10032, USA
    Psychiatr Genet 19:186-94. 2009
    ..This study was designed to understand some of the barriers to recruitment...
  13. ncbi Familial aggregation of illness chronicity in recurrent, early-onset major depression pedigrees
    Francis M Mondimore
    Johns Hopkins Hospital, Meyer 3 181, 600 North Wolfe St, Baltimore, MD 21287, USA
    Am J Psychiatry 163:1554-60. 2006
    ..The authors used a large sample collected for genetic studies to determine whether a chronic course of illness defines a familial clinical subtype in major depressive disorder...
  14. ncbi Reproductive cycle-associated mood symptoms in women with major depression and bipolar disorder
    Jennifer L Payne
    Department of Psychiatry, Women s Mood Disorders Center, The Johns Hopkins Hospital, 600 North Wolfe Street Meyer 3 181, Baltimore, MD 21287 7381, United States
    J Affect Disord 99:221-9. 2007
    ..We hypothesized that symptoms would correlate with each other across a woman's reproductive life span in both major depression (MDD) and bipolar I disorder (BP)...
  15. pmc A comparison of the familiality of chronic depression in recurrent early-onset depression pedigrees using different definitions of chronicity
    Francis M Mondimore
    Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
    J Affect Disord 100:171-7. 2007
    ..Because familial clustering is one component of diagnostic validity we compared family clustering of chronicity as defined in the DSM-IV to that of chronicity determined by an assessment of lifetime course of depressive illness...
  16. ncbi Genetics of recurrent early-onset major depression (GenRED): final genome scan report
    Peter Holmans
    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 701A Welch Rd, Suite 3325, Palo Alto, CA 94304 5797, USA
    Am J Psychiatry 164:248-58. 2007
    ....
  17. ncbi Genetics of recurrent early-onset major depression (GenRED): significant linkage on chromosome 15q25-q26 after fine mapping with single nucleotide polymorphism markers
    Douglas F Levinson
    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 701A Welch Rd, Suite 3325, Palo Alto, CA 94304 5797, USA
    Am J Psychiatry 164:259-64. 2007
    ....
  18. ncbi Investigating the role of p11 (S100A10) sequence variation in susceptibility to major depression
    Ranjana Verma
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Am J Med Genet B Neuropsychiatr Genet 144:1079-82. 2007
    ..2%, P = 0.15). None of the tag SNPs showed any evidence of association. Our results do not support a major role for either common or rare p11 SNPs with MDD. Several limitations of the study are discussed...
  19. pmc Linkage disequilibrium mapping of a chromosome 15q25-26 major depression linkage region and sequencing of NTRK3
    Ranjana Verma
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Biol Psychiatry 63:1185-9. 2008
    ..Here we present initial linkage-disequilibrium (LD) fine mapping of this signal and sequence analysis of NTRK3 (neurotrophic receptor kinase-3), a biologically plausible candidate gene...
  20. pmc Depression
    Myrna Weissman
    Department of Psychiatry, College of Physicians and Surgeons and Mailman School of Public Health, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA
    Ann Epidemiol 19:264-7. 2009
    ..I hope the new generation will have the wonderful opportunities I have had...
  21. pmc A recessive genetic model and runs of homozygosity in major depressive disorder
    Robert A Power
    MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King s College London, London, United Kingdom
    Am J Med Genet B Neuropsychiatr Genet 165:157-66. 2014
    ..They highlight the sensitivity of the ROH method to spurious associations, and the need to carefully control for potential confounds in such analyses. We found no strong evidence for a recessive model underlying MDD...