Lencz Todd, Lambert Christophe, DeRosse Pamela, Burdick Katherine E, Morgan T Vance, Kane John M, Kucherlapati Raju, Malhotra Anil K
Department of Psychiatry Research, Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, 75-59 263rd Street, Glen Oaks, NY 11004, USA.
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19942-7. doi: 10.1073/pnas.0710021104. Epub 2007 Dec 5.
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.
具有进化意义的选择性清除可能导致远交群体个体中出现长片段的纯合多态性。我们开发了全基因组纯合性关联（WGHA）方法，以在健康个体中表征这一现象，并利用这一基因组特征来识别精神分裂症（SCZ）的遗传风险位点。将WGHA应用于178例SCZ患者和144例在50万个标记处进行基因分型的健康对照，我们发现长度从200 kb到15 mb不等的纯合片段（ROH）在无关的白种人中很常见。健康受试者中常见ROH的特性，包括染色体定位和非祖先单倍型的存在，与先前确定处于选择压力下区域的报告一致。对使用相同标记进行基因分型的多民族HapMap样本的分析进一步支持了这一解释。ROH在SCZ患者中明显更常见，一组9个ROH显著区分了患者和对照。这9个“风险ROH”中有4个包含与SCZ相关的基因或与之相邻（NOS1AP、ATF2、NSF和PIK3C3）。这些风险ROH中有几个在健康受试者中非常罕见，这表明相对高外显率的隐性效应可能解释了SCZ遗传易感性的一部分。其他风险ROH具有在健康个体中也很常见的单倍型，这可能表明存在平衡选择的来源。
