Elsevier

Biological Psychiatry

Volume 71, Issue 1, 1 January 2012, Pages 6-14
Biological Psychiatry

Archival Report
High Dimensional Endophenotype Ranking in the Search for Major Depression Risk Genes

https://doi.org/10.1016/j.biopsych.2011.08.022Get rights and content

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.

Section snippets

Participants

A total of 1,122 Mexican American individuals from extended pedigrees (71 families, average size 14.9 [1–87] people) were included in the analysis. Participants were 64% female and ranged in age from 18 to 97 (mean ± SD 47.11 ± 14.2) years. Individuals in this cohort have actively participated in research for over 18 years and were randomly selected from the community with the constraints that they are of Mexican American ancestry, part of a large family, and live within the San Antonio region

Heritability of Recurrent Major Depression

Two hundred fifteen individuals met criteria for lifetime rMDD (19% of the sample; 73% female subjects). Eighty-six individuals were clinically depressed at the time of the assessment. The estimated heritability for lifetime rMDD was h2 = .463 (standard error ± .12), p = 4.0 × 10−6. We previously demonstrated that this heritability estimate is not significantly influenced by common environmental factors as indexed by shared household (21). Additionally, there was no evidence for dominance (p =

Discussion

Our results demonstrate the utility of the ERV approach for formally identifying endophenotypes in high-dimensional data and provide a novel genome-wide significant QTL for recurrent major depression. Bivariate genetic analyses including a quantitative endophenotype and disease risk significantly improved QTL detection over that observed utilizing diagnosis alone. These results may reflect the improved statistical sensitivity of quantitative over qualitative traits or that endophenotypes index

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