High dimensional endophenotype ranking in the search for major depression risk genes

David C. Glahn, Joanne E. Curran, Anderson M. Winkler, Melanie A. Carless, Jack W. Kent, Jac C. Charlesworth, Matthew P. Johnson, Harald H H Göring, Shelley A. Cole, Thomas D. Dyer, Eric K. Moses, Rene L Olvera, Peter Kochunov, Ravi Duggirala, Peter T Fox, Laura Almasy, John Blangero

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Background: Despite overwhelming evidence that major depression is highly heritable, recent studies have localized only a single depression-related locus reaching genome-wide significance and have yet to identify a causal gene. Focusing on family-based studies of quantitative intermediate phenotypes or endophenotypes, in tandem with studies of unrelated individuals using categorical diagnoses, should improve the likelihood of identifying major depression genes. However, there is currently no empirically derived statistically rigorous method for selecting optimal endophentypes for mental illnesses. Here, we describe the endophenotype ranking value, a new objective index of the genetic utility of endophenotypes for any heritable illness. Methods: Applying endophenotype ranking value analysis to a high-dimensional set of over 11,000 traits drawn from behavioral/neurocognitive, neuroanatomic, and transcriptomic phenotypic domains, we identified a set of objective endophenotypes for recurrent major depression in a sample of Mexican American individuals (n = 1122) from large randomly selected extended pedigrees. Results: Top-ranked endophenotypes included the Beck Depression Inventory, bilateral ventral diencephalon volume, and expression levels of the RNF123 transcript. To illustrate the utility of endophentypes in this context, each of these traits were utlized along with disease status in bivariate linkage analysis. A genome-wide significant quantitative trait locus was localized on chromsome 4p15 (logarithm of odds = 3.5) exhibiting pleiotropic effects on both the endophenotype (lymphocyte-derived expression levels of the RNF123 gene) and disease risk. Conclusions: The wider use of quantitative endophenotypes, combined with unbiased methods for selecting among these measures, should spur new insights into the biological mechanisms that influence mental illnesses like major depression.

Original languageEnglish (US)
Pages (from-to)6-14
Number of pages9
JournalBiological Psychiatry
Volume71
Issue number1
DOIs
StatePublished - Jan 1 2012

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Endophenotypes
Depression
Genes
Genome
Diencephalon
Quantitative Trait Loci
Pedigree
Lymphocytes
Phenotype
Equipment and Supplies

Keywords

  • Endophenotype
  • endophenotype ranking
  • family studies
  • linkage
  • major depression
  • recurrent major depression

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Glahn, D. C., Curran, J. E., Winkler, A. M., Carless, M. A., Kent, J. W., Charlesworth, J. C., ... Blangero, J. (2012). High dimensional endophenotype ranking in the search for major depression risk genes. Biological Psychiatry, 71(1), 6-14. https://doi.org/10.1016/j.biopsych.2011.08.022

High dimensional endophenotype ranking in the search for major depression risk genes. / Glahn, David C.; Curran, Joanne E.; Winkler, Anderson M.; Carless, Melanie A.; Kent, Jack W.; Charlesworth, Jac C.; Johnson, Matthew P.; Göring, Harald H H; Cole, Shelley A.; Dyer, Thomas D.; Moses, Eric K.; Olvera, Rene L; Kochunov, Peter; Duggirala, Ravi; Fox, Peter T; Almasy, Laura; Blangero, John.

In: Biological Psychiatry, Vol. 71, No. 1, 01.01.2012, p. 6-14.

Research output: Contribution to journalArticle

Glahn, DC, Curran, JE, Winkler, AM, Carless, MA, Kent, JW, Charlesworth, JC, Johnson, MP, Göring, HHH, Cole, SA, Dyer, TD, Moses, EK, Olvera, RL, Kochunov, P, Duggirala, R, Fox, PT, Almasy, L & Blangero, J 2012, 'High dimensional endophenotype ranking in the search for major depression risk genes', Biological Psychiatry, vol. 71, no. 1, pp. 6-14. https://doi.org/10.1016/j.biopsych.2011.08.022
Glahn DC, Curran JE, Winkler AM, Carless MA, Kent JW, Charlesworth JC et al. High dimensional endophenotype ranking in the search for major depression risk genes. Biological Psychiatry. 2012 Jan 1;71(1):6-14. https://doi.org/10.1016/j.biopsych.2011.08.022
Glahn, David C. ; Curran, Joanne E. ; Winkler, Anderson M. ; Carless, Melanie A. ; Kent, Jack W. ; Charlesworth, Jac C. ; Johnson, Matthew P. ; Göring, Harald H H ; Cole, Shelley A. ; Dyer, Thomas D. ; Moses, Eric K. ; Olvera, Rene L ; Kochunov, Peter ; Duggirala, Ravi ; Fox, Peter T ; Almasy, Laura ; Blangero, John. / High dimensional endophenotype ranking in the search for major depression risk genes. In: Biological Psychiatry. 2012 ; Vol. 71, No. 1. pp. 6-14.
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