Major depression is a serious psychiatric disorder impacting the lives of millions of Americans. The gene DISC1 has been linked to this disorder by translocation in a single Scottish family as well as being supported by functional analyses of the gene prominent in neural development. We propose to carry out whole genome sequencing on 40 members of the original translocation family to identify possible variants that modify the effec of the translocation on phenotype as well as examine epigenetic differences in those that bear the translocation. We will also carry out genetic analyses by both genotyping and targeted sequencing to look for genetic differences in DISC1 and its core pathway genes in a total of nearly 10,000 people. Lastly, we will examine blood samples from some of those individuals with variants in the core pathway to determine if these variants change gene expression.

Public Health Relevance

Major depression is a significant public health problem in the U.S. and throughout the world. In an effort to better understand the mechanism of the illness we propose to analyze the genetic variation in a rare family heavily burdened by the disorder and then examine variants associated with those found in that family in a much larger set of unrelated people. Our ultimate goal is to identify variants that may be valuable to diagnose and guide treatment options for those with the disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ETTN-L (03))
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Senthil, Geetha
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Cold Spring Harbor Laboratory
Cold Spring Harbor
United States
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Ryan, Niamh M; Lihm, Jayon; Kramer, Melissa et al. (2018) DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders. Mol Psychiatry 23:2254-2265
Teng, S; Thomson, P A; McCarthy, S et al. (2018) Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia. Mol Psychiatry 23:1270-1277
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