Commentary: The origins of intellectual disability

Despite the importance and prevalence of intellectual disability (ID), its origins have not been well understood until now. Lichtenstein et al. report in this issue findings from a population-based sample four times larger than all previous family studies of ID put together (Lichtenstein et al., 2022). From more than four million people, 37,787 individuals were identified with ID. Relative risks (RRs) are reported for relatives of ID probands (55,000 first-degree, 55,000 second-degree, and 170,000 third-degree) as compared with matched relatives of individuals without ID. These relatives plus 400 pairs of twins in which at least one twin was diagnosed with ID yield an astonishing estimate of 95% heritability with no evidence for shared environmental influence in their model. Another important finding is that maternal half-siblings of ID individuals were at greater risk than paternal half-siblings, a maternal effect that could indicate X-chromosome linkage. Finally, profound and severe ID is etiologically distinct from the normal distribution, due in part to noninherited (de novo) genetic mutations and chromosomal abnormalities. However, 90% of individuals with ID are moderate or mild, and these represent the low end of the normal distribution of genetic influence on cognitive ability, which has important implications for DNA research on ID.