Chunk #11 — Arguments against the rare allele model — Sibling recurrence rates are greater than expected by the postulated effect sizes of rare variants
Heritability of disease is very often inferred from elevated sibling recurrence rates relative to incidence in unrelated individuals. Intuitively, if a disease has a prevalence of 1% in the general population, but 50% of siblings are affected, then the odds are elevated 50-fold in the family, whereas a single segregating rare variant with a 5-fold effect would only be expected to result in disease for 5% of carrier individuals. Sibling recurrence rates are generally much higher than can be attributed to rare variants with the postulated effect sizes17. If rare variants are contributing then they are doing so in the context of many other genetic variants in the pedigrees, as shown by a recent analysis of schizophrenia genetics54. Under multiplicative models, disease may cluster in families due to segregation of multiple rare variants that happen to be brought together in the pedigree. Nevertheless, the rare allele model must not only explain association data in populations, but also fit demographic distributions of disease within and among families, and there is little theory supporting the claim that they can do both55–57.
