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Runs of Homozygosity Reveal Highly Penetrant Recessive Loci in Schizophrenia

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Runs of Homozygosity Reveal Highly Penetrant Recessive Loci in Schizophrenia Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia Todd Lencz*†‡§, Christophe Lambert¶, Pamela DeRosse*, Katherine E. Burdick*†‡, T. Vance Morganʈ, John M. Kane*†‡, Raju Kucherlapatiʈ**, and Anil K. Malhotra*†‡ *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; ʈHarvard 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) Evolutionarily significant selective sweeps may result in long date genes are inherently limited in scope. By contrast, WGHA stretches of homozygous polymorphisms in individuals from out- (described in detail below) presents an opportunity for rapidly bred populations. We developed whole-genome homozygosity identifying susceptibility loci broadly across the genome, yet with association (WGHA) methodology to characterize this phenome- resolution sufficient to implicate a circumscribed set of candidate non in healthy individuals and to use this genomic feature to genes. WGHA is designed to be sensitive for detecting loci under identify genetic risk loci for schizophrenia (SCZ). Applying WGHA selective pressure, and recent data suggest that signatures of to 178 SCZ cases and 144 healthy controls genotyped at 500,000 evolutionary selection may be strongly observed in genes regulating markers, we found that runs of homozygosity (ROHs), ranging in neurodevelopment (5, 6). Thus, WGHA may be particularly effec- size from 200 kb to 15 mb, were common in unrelated Caucasians. tive for SCZ, which is thought to have a primary pathophysiological Properties of common ROHs in healthy subjects, including chro- basis in abnormal neurodevelopmental processes (7). mosomal location and presence of nonancestral haplotypes, con- Regions of extended homozygosity across large numbers of verged with prior reports identifying regions under selective consecutive SNPs form the basis of WGHA analysis. In general, pressure. This interpretation was further supported by analysis of extent of homozygosity is a function of LD within a chromosomal multiethnic HapMap samples genotyped with the same markers. region, which in turn is a function of recombination rates and ROHs were significantly more common in SCZ cases, and a set of population history (8–10). Size and structure of LD blocks vary nine ROHs significantly differentiated cases from controls. Four of widely across the genome and across populations (11), and regions these 9 ‘‘risk ROHs’’ contained or neighbored genes associated of extensive long-range LD may be indicative of partially complete with SCZ (NOS1AP, ATF2, NSF, and PIK3C3). Several of these risk selective sweeps of functional significance (12). For example, ROHs were very rare in healthy subjects, suggesting that recessive variants of the extended haplotype homozygosity test (13) have effects of relatively high penetrance may explain a proportion of been used to examine identity-by-descent across unrelated chro- the genetic liability for SCZ. Other risk ROHs feature haplotypes mosomes in HapMap (14) and other population samples, identi- that are also common in healthy individuals, possibly indicating a fying known loci under selection (e.g., LCT in Europeans, see refs. source of balancing selection. 15 and 16). A logical consequence of such identity across unrelated chromosomes is that long stretches of homozygosity may be ob- genomewide ͉ selection ͉ haplotype ͉ HapMap ͉ susceptibility served in healthy individuals from outbred populations lacking any known consanguineous parentage (17, 18). However, the relative he recent development of microarray platforms, capable of commonality of this phenomenon has not been systematically Tgenotyping hundreds of thousands of SNPs, has provided an documented in large datasets at high resolution. Moreover, al- opportunity to rapidly identify novel susceptibility genes for com- though homozygosity mapping has successfully identified disease plex phenotypes. Studies employing genotyping microarrays have loci in pedigrees marked by Mendelian illness (19), the ability of typically used a whole-genome association (WGA) approach, in such a method to detect susceptibility loci in common disease has which each SNP is examined individually for association with not been examined in a case-control study. We present data disease (1); multiple testing requires that statistical thresholds for addressing both normal patterns of homozygosity and use of these WGA approach 10Ϫ7 or lower (2). Given the presumably polygenic patterns in WGHA mapping of SCZ. nature of complex illness, this conservative strategy inevitably Results results in false negatives in the search for susceptibility genes (3). At the same time, structural properties of WGA datasets, including The sample of 178 unrelated Caucasian SCZ cases and 144 unre- patterns of linkage disequilibrium (LD), have not yet been ex- lated Caucasian, sex-matched controls were ascertained and psy- ploited in these analyses. Consequently, we developed an analytic chiatrically diagnosed at a single geographic site (the Zucker approach, termed whole-genome homozygosity association Hillside Hospital, ZHH), as described in ref. 20. DNA extracted ϭ (WGHA), which first identifies patterned clusters of SNPs dem- from whole blood was assayed at 500,568 SNPs (mean spacing 5.8 onstrating extended homozygosity and then employs both genome wide and regionally specific statistical tests for association to Author contributions: T.L., J.M.K., and A.K.M. designed research; T.L., T.V.M., R.K., and disease. In the present study, we used WGHA in a case-control A.K.M. performed research; T.L. and C.L. contributed new reagents/analytic tools; T.L., C.L., dataset of patients with schizophrenia (SCZ) and healthy volun- P.D., K.E.B., and A.K.M. analyzed data; and T.L. and A.K.M. wrote the paper. Ϸ teers, genotyped at 500,000 SNPs, to detect novel susceptibility Conflict of interest statement: C.L. is employed with Golden Helix and holds Ͼ5% equity in loci for SCZ. the company. Golden Helix subsequently developed a commercial version of the data SCZ is a disease with estimated lifetime morbid risk approaching analysis methodologies described in this paper. 1% worldwide. Although genetic epidemiologic studies have re- Freely available online through the PNAS open access option. vealed high heritability estimates (70–80%) for SCZ, identification §To whom correspondence should be addressed. E-mail: [email protected]. of susceptibility genes remains challenging. As with other complex This article contains supporting information online at www.pnas.org/cgi/content/full/ diseases, linkage studies have revealed multiple candidate regions 0710021104/DC1. with modest LOD scores (4), whereas studies of individual candi- © 2007 by The National Academy of Sciences of the USA 19942–19947 ͉ PNAS ͉ December 11, 2007 ͉ vol. 104 ͉ no. 50 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0710021104 Downloaded by guest on September 24, 2021 (144 ؍ Table 1. List of nine ROHs with frequency >25% in the healthy cohort (n No. of deletions/ Start End Length, No. of Control, iHS Tajima Fst duplications/ ROH Chr (B35) (B35) bp SNPs n (%) max D max max hotspots Core SNP Allele roh172 8 42588087 53273605 10,685,518 852 77 (53.5) 3.90 2.00 0.90 0/6/32 rs11136221 C roh134 6 26216147 29800284 3,584,137 489 52 (36.1) 2.40 1.50 0.52 0/3/13 rs2859365 A roh89 4 32428277 34888919 2,460,642 252 52 (36.1) 3.50 2.40 0.62 9/2/17 rs7340793 G roh241 11 46212732 49874378 3,661,646 323 48 (33.3) 2.30 1.75 0.70 11/1/3 rs10838852 T roh291 14 65475183 67065410 1,590,227 197 47 (32.5) 2.50 2.75 0.99 0/0/9 rs2053149 C roh171 8 33590815 36749387 3,158,572 443 41 (28.5) 0.60 2.80 0.42 0/0/19 rs2719307 A roh238 11 37492528 40090659 2,598,131 386 39 (27.1) 1.10 5.10 0.45 0/0/25 rs7938730 T roh275 12 109752647 111733445 1,980,798 205 37 (25.7) 1.10 1.80 0.22 0/0/8 rs17696736 G roh125 5 129481382 132022568 2,541,186 286 36 (25.0) 1.20 1.25 0.65 1/1/12 rs31251 A Chromosomal coordinates listed from National Center for Biotechnology Information (NCBI) build 35. Columns 8–10 represent maximal values for alternate metrics of positive selection, derived from Haplotter (ref. 15, http://hg-wen.uchicago.edu/selection/haplotter.htm). Number of deletions, duplications, and recombination hotspots derived from HapMap version 21a (ref. 14, http://hapmap.org). Alleles are listed consistent with strand as displayed in HapMap v21a. Note that all alleles are designated as derived alleles according to dbSNP build 127 (except for rs7340793, for which ancestral/derived alleles are not available). kb; mean heterozygosity ϭ 27%). After performance of quality P ϭ 2.8 ϫ 10Ϫ8); these correlations are comparable to the inter- control procedures (see Methods for details), 444,763 autosomal correlation of maximal iHS and D for the same regions (r ϭ 0.30, (and pseudoautosomal) SNPs demonstrating genotype call repli- P ϭ 1.3 ϫ 10Ϫ8). cability Ͼ99.4% were available for WGHA analysis. The final columns of Table 1 indicate the ‘‘core’’ SNP and allele demonstrating the maximal degree of overlap across all carriers of Identification of Common ROHs in ZHH Subjects. The first step of a given ROH. Extent of allelic/haplotypic sharing is variable be- WGHA analysis is the identification of runs of homozygosity cause ROHs can vary in length across individual subjects with (ROHs) in each subject, defined in the present study as any window differing degrees of overlap and extension (see Methods); however, of 100 or more consecutive SNPs on a single chromosome not in general, common ROHs represent carriers of the same alleles.
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