Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia

Abstract

Evolutionarily significant selective sweeps may result in long stretches of homozygous polymorphisms in individuals from outbred populations. We developed whole-genome homozygosity association (WGHA) methodology to characterize this phenomenon in healthy individuals and to use this genomic feature to identify genetic risk loci for schizophrenia (SCZ). Applying WGHA to 178 SCZ cases and 144 healthy controls genotyped at 500,000 markers, we found that runs of homozygosity (ROHs), ranging in size from 200 kb to 15 mb, were common in unrelated Caucasians. Properties of common ROHs in healthy subjects, including chromosomal location and presence of nonancestral haplotypes, converged with prior reports identifying regions under selective pressure. This interpretation was further supported by analysis of multiethnic HapMap samples genotyped with the same markers. ROHs were significantly more common in SCZ cases, and a set of nine ROHs significantly differentiated cases from controls. Four of these 9 "risk ROHs" contained or neighbored genes associated with SCZ (NOS1AP, ATF2, NSF, and PIK3C3). Several of these risk ROHs were very rare in healthy subjects, suggesting that recessive effects of relatively high penetrance may explain a proportion of the genetic liability for SCZ. Other risk ROHs feature haplotypes that are also common in healthy individuals, possibly indicating a source of balancing selection.

Fig. 1.

Graphical depiction of statistical comparisons (SCZ vs. control) at individual SNPs within roh172 on chromosome 8q. Chromosomal context is depicted in ideogram at the top. Gene location (build 35 coordinates) for SNTG1 is depicted immediately below the ideogram. Coding region of SNTG1 is indicated by a red dotted line; exons are indicated by horizontal lines. The jagged line depicts −log₁₀ P values for case-control comparisons at each binarized SNP.