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.genomewide ͉ selection ͉ haplotype ͉ HapMap ͉ susceptibility

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

“…2 To this gene list of 786 genes, we then added 2 genes identified by runs of homozygosity in schizophrenia, 15 and 21 genes revealed by structural breakage of microdeletions and duplications 16 to the SZ susceptibility list. This compilation produced a list of 809 of genes, which we used for our further analyses (data not shown).…”

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia

“…Previous studies have used SNP microarrays to identify multi-megabase runs of homozygosity (ROH), that likely reflect autozygosity arising from a degree of recent inbreeding. 13,14 A study of 9388, predominantly European, SCZ cases and 12 456 controls demonstrated a significant positive correlation between the extent of ROH per individual and the disease risk. 15 However, they did not identify any significant individual loci.…”

The discovery of human genetic variations and their use as disease markers: past, present and future

“…Interestingly, genome-wide homozygosity mapping approaches have also been applied to dissect the genetic basis of complex diseases and have successfully identified a number of susceptibility loci for schizophrenia. 22 Conversely, short indels have not been directly interrogated in GWAS, but how much they can be tagged indirectly through LD by the SNPs in genotyping arrays is unclear. Unlike CNVs and homozygosity mapping, which can be studied by SNPs genotyping arrays, no high-throughput method has been designed and developed to investigate short indels on a genome-wide scale.…”

“…Although the biomedical significance of regions of homozygosity to complex diseases remains largely unexplored, some schizophrenia studies have already shown significant differences in homozygosity regions between cases and controls in a genome-wide study. 22 More importantly is that the study has demonstrated the feasibility of using the homozygosity mapping approach to identify susceptibility loci and genes for complex diseases. This also highlights the need to further investigate and catalog the extent of LOH and homozygosity in the human genome.…”

“…[11][12][13][14] Furthermore, these genetic variations were also found to be associated with various human diseases, including monogenic and complex diseases. [14][15][16][17][18][19][20][21][22] Presently, research in genetic variations is drawing much attention and effort from the genetics community, as evident from the initiation of the 1000 Genomes Project, which has a major aim to construct the most detailed map of genetic variations in the human genome. 23,24 The non-SNP genetic variations certainly have the potential of becoming the next generation genetic markers in human genetic and disease gene mapping studies.…”