Characterizing the Extent of Human Genetic Variation for Performance‐Related Traits

Blangero, John; Kent, Jack W.

doi:10.1002/9781444327335.ch3

Cited by 4 publications

(1 citation statement)

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“…Rare variants represent a partial explanation for the missing heritability paradox as their abundance and their expected genetic effect sizes are much higher than common variants [ 15 ]. Large extended pedigrees, like those in the GAW18 cohort, increase the probability of detecting rare variant effects, as variants that are rare in the population may be enriched by segregation in specific lineages [ 16 ]. Conventional genome-wide association-style multiple testing of the immense number of rare variants would require the use of stringent significance thresholds and reduce power.…”

Section: Discussionmentioning

confidence: 99%

Pedigree-based random effect tests to screen gene pathways

et al. 2014

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The new generation of sequencing platforms opens new horizons in the genetics field. It is possible to exhaustively assay all genetic variants in an individual and search for phenotypic associations. The whole genome sequencing approach, when applied to a large human sample like the San Antonio Family Study, detects a very large number (>25 million) of single nucleotide variants along with other more complex variants. The analytical challenges imposed by this number of variants are formidable, suggesting that methods are needed to reduce the overall number of statistical tests. In this study, we develop a single degree-of-freedom test of variants in a gene pathway employing a random effect model that uses an empirical pathway-specific genetic relationship matrix as the focal covariance kernel. The empirical pathway-specific genetic relationship uses all variants (or a chosen subset) from gene members of a given biological pathway. Using SOLAR's pedigree-based variance components modeling, which also allows for arbitrary fixed effects, such as principal components, to deal with latent population structure, we employ a likelihood ratio test of the pathway-specific genetic relationship matrix model. We examine all gene pathways in KEGG database gene pathways using our method in the first replicate of the Genetic Analysis Workshop 18 simulation of systolic blood pressure. Our random effect approach was able to detect true association signals in causal gene pathways. Those pathways could be easily be further dissected by the independent analysis of all markers.

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Section: Discussionmentioning

confidence: 99%