The fourth argument against rare variant effects is a demographic one, namely the changing prevalence of so many chronic diseases in a span of just two or three generations, and/or the known impact of environmental variables on risk. For example, diabetes and heart disease have greatly increased in incidence in India and China in the past 10 years60,61, an epidemiological transition that at best implies a change in penetrance of genetic effects attributable to any class of variant, rare or common, in the contemporary environment. Schizophrenia, a disease with very high heritability (inferred from twin studies) and for which very few replicated GWAS hits have been identified despite extensive scans, nevertheless shows such demographic influences as whether the parents live in rural or urban areas (disease rates are elevated in children born after migration to cities)62. Paternal age effects on psychological disease63 might be attributed to elevated mutation rates in sperm, but other hypotheses are equally compatible with the data, and maternal age effects operate in the opposite direction as younger mothers have higher likelihoods of having affected children64. In other words, rare variants alone cannot explain the demographic distribution of disease incidence.
