Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia

doi:10.1073/pnas.0710021104

Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia

*Department of Psychiatry Research, Zucker Hillside Hospital, North Shore–Long Island Jewish Health System, 75-59 263rd Street, Glen Oaks, NY 11004;
^†The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;
^‡Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Belfer Room 403, Bronx, NY 10461;
^¶Golden Helix, Inc., 716 South 20th Avenue, Suite 102, Bozeman, MT 59718;
^‖Harvard Partners Center for Genetics and Genomics, 65 Landsdowne Street, Cambridge, MA 02139; and
**Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115

Communicated by James D. Watson, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, October 22, 2007 (received for review July 10, 2007)

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.

Footnotes

^§To whom correspondence should be addressed. E-mail: lencz{at}lij.edu
Author contributions: T.L., J.M.K., and A.K.M. designed research; T.L., T.V.M., R.K., and A.K.M. performed research; T.L. and C.L. contributed new reagents/analytic tools; T.L., C.L., P.D., K.E.B., and A.K.M. analyzed data; and T.L. and A.K.M. wrote the paper.
Conflict of interest statement: C.L. is employed with Golden Helix and holds >5% equity in the company. Golden Helix subsequently developed a commercial version of the data analysis methodologies described in this paper.
This article contains supporting information online at www.pnas.org/cgi/content/full/0710021104/DC1.
Freely available online through the PNAS open access option.