Knowns and unknowns for psychophysiological endophenotypes: integration and response to commentaries.
- Authors
- Iacono, William G; Vaidyanathan, Uma; Vrieze, Scott I; Malone, Stephen M
- Year
- 2014
- Journal
- Psychophysiology
- PMID
- 25387720
- DOI
- 10.1111/psyp.12358
- PMCID
- PMC4231488
We review and summarize seven molecular genetic studies of 17 psychophysiological endophenotypes that comprise this special issue of Psychophysiology, address criticisms raised in accompanying Perspective and Commentary pieces, and offer suggestions for future research. Endophenotypes are polygenic, and possibly influenced by rare genetic variants. Because they are not simpler genetically than clinical phenotypes, they are unlikely to assist gene discovery for psychiatric disorder. Once genetic variants for clinical phenotypes are identified, associated endophenotypes are likely to provide valuable insights into the psychological and neural mechanisms important to disorder pathology. This special issue provides a foundation for informed future steps in endophenotype genetics, including the formation of large sample consortia capable of fleshing out the many genetic variants contributing to individual differences in psychophysiological measures.
Summary of heritability results from biometric analyses and genome-wide complex trait analyses (GCTA) for each endophenotype. The x axis indicates the psychophysiological variable, while the y axis shows the percentage of variance accounted for. “Biometric A” (black bars) denotes the estimate of the additive genetic component obtained in conventional family-based biometric models of each endophenotype. “GCTA Family” (light gray bars) represents GCTA estimates of endophenotypic variance accounted for by the combined effect of all 527,829 single nucleotide polymorphisms (SNPs) used in GWAS analyses with all MTFS participants included. This GCTA model accounts for the effect of all causal variants, including nonadditive genetic effects, but the estimate provided removes the effect contributed by shared environmental influence. “GCTA Median” (dark gray bars) represents the average GCTA value for each endophenotype based on the GCTA estimates for unrelated people. It indicates the additive heritability conferred by all the SNPs on the genotyping array using two different GCTA models (based on unweighted SNPs or weighting SNPs by local linkage disequilibrium patterns) and three different subsamples of unrelated participants (using genetic relatedness matrix values of .025, .05, and .10). The P3 genetic factor score is not included in the figure because it represents only genetic variance, i.e., has a biometric heritability of 100%.
| # | Section | Preview |
|---|---|---|
| 40 | Conclusions: Limits of the Knowns and Unknowns — Endophenotypes Are Massively Polygenic | Our findings suggest that, like other complex traits, endophenotypes are polygenic, reflecting the… |
| 41 | Conclusions: Limits of the Knowns and Unknowns — Endophenotypes Likely Reflect the Influence of Rare Variants | Polygenic inheritance does not preclude the possibility, perhaps strong, of rare variants with large… |
| 42 | Conclusions: Limits of the Knowns and Unknowns — Endophenotypes Will Not Simplify Gene-Finding for Psychiatric Disorder | The promise of endophenotypes has been oversold. Even if endophenotypes are conceptually simpler… |
| 43 | Conclusions: Limits of the Knowns and Unknowns — Endophenotype Genetics Might Contribute Important Biologic Insights for Psychiatric Disorders | As de Geus (2010; 2014, this issue) and Munafò and Flint (2014, this issue) have noted, the value… |
| 44 | Conclusions: Limits of the Knowns and Unknowns — Next Steps | A theme echoed repeatedly throughout the special issue articles and commentaries is the advantage of… |
| 45 | Conclusions: Limits of the Knowns and Unknowns — Next Steps | Our results suggest that the focus of endophenotypic theory and research should change, moving away… |
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