Population genetic theory suggests an explanation for the paucity of variants explaining a large proportion of disease predisposition, in that decreased reproductive fitness should typically act to reduce the frequencies of high-risk variants. This might explain the relative lack of variants detected so far for some neuropsychiatric conditions, such as autism spectrum disorders, given their low reproductive fitness25. Yet for a condition such as type 1 diabetes, which has a similar prevalence, familial risk, early onset and poor reproductive fitness (at least before the discovery of insulin therapy), more than 40 loci have already been reported; this might be because the overall sample sizes studied in type 1 diabetes have been very large26,27. Present-day reproductive fitness may correlate poorly with the forces that have shaped variation throughout human evolution; moreover focusing on the reproductive effects of a single disease ignores the pleiotropic effects (effects of the same variant on multiple characteristics or disease risks) of multiple alleles influencing that condition simultaneously with many other conditions28.
