Contribution of rare variant alleles to prostate cancer heritability

Considering “how much diverse single-nucleotide variants (SNVs) contribute to heritability”, there are three classes: >95% of each common SNV usually elicits small effects; <5% of each low-frequency SNV usually elicits larger effects; and <0.5% of each rare SNV can elicit large effects. Low- and rare-frequency SNVs in coding regions usually contribute the most to phenotype (large-effect variants). The [attached] report concerns the latter rare-variant class.

 Mancuso et al. [reference below] report targeted sequencing of 63 known prostate cancer risk regions––in a multi-ancestry study of 9,237 men (I don’t know why women were excluded from this study?) and use the data to explore the contribution of low-frequency variation to disease risk.  Authors showed that SNVs with minor allele frequencies (MAFs) of 0.1–1% explain a substantial fraction of prostate cancer risk in men of African ancestry. They estimated that these SNVs account for 0.12 (standard error = 0.05) of variance in risk (~42% of the variance contributed by SNVs with MAFs of 0.1–50%).

 The contribution of low-frequency variants is much larger than the fraction of neutral variation due to SNVs in this class––implying that natural selection has driven down the frequency of many prostate cancer risk alleles. They stimated that the coupling between selection and allelic effects at 0.48 (95% confidence interval [0.19, 0.78], using the Eyre-Walker model). These results indicate that rare variants make a disproportionate contribution to genetic risk for prostate cancer and suggest the possibility that rare variants may also have an outsize effect on other common traits (i.e. quantitative human traits, described in a preceding post).

 Nat Genet Jan 2o16; 48: 30–35

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