title: High dimensional endophenotype ranking in the search for major depression risk genes.
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.
authors: Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, 200 Retreat Avenue, Hartford, CT 06106, USA. david.glahn@yale.edu
authors: David C
authors: DC
authors: Glahn
authors: Joanne E
authors: JE
authors: Curran
authors: Anderson M
authors: AM
authors: Winkler
authors: Melanie A
authors: MA
authors: Carless
authors: Jack W
authors: JW
authors: Kent
authors: Jac C
authors: JC
authors: Charlesworth
authors: Matthew P
authors: MP
authors: Johnson
authors: Harald H H
authors: HH
authors: Göring
authors: Shelley A
authors: SA
authors: Cole
authors: Thomas D
authors: TD
authors: Dyer
authors: Eric K
authors: EK
authors: Moses
authors: Rene L
authors: RL
authors: Olvera
authors: Peter
authors: P
authors: Kochunov
authors: Ravi
authors: R
authors: Duggirala
authors: Peter T
authors: PT
authors: Fox
authors: Laura
authors: L
authors: Almasy
authors: John
authors: J
authors: Blangero
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D003072:Cognition Disorders; D003865:Major Depressive Disorder / Q000150:complications / Q000235:genetics* / Q000473:pathology; D058068:Endophenotypes; D005192:Family Health; D005260:Female; D020869:Gene Expression Profiling; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D017058:Mexican Americans / Q000235:genetics; D008875:Middle Aged; D009483:Neuropsychological Tests; D020411:Oligonucleotide Array Sequence Analysis; D011569:Psychiatric Status Rating Scales; D040641:Quantitative Trait Loci; D012306:Risk; D055815:Young Adult