Bodea Corneliu A, Middleton Frank A, Melhem Nadine M, Klei Lambertus, Song Youeun, Tiobech Josepha, Marumoto Pearl, Yano Victor, Faraone Stephen V, Roeder Kathryn, Myles-Worsley Marina, Devlin Bernie, Byerley William
Department of Statistics, Carnegie Mellon University, Pittsburgh, Pa, USA.
Department of Psychiatry, SUNY Upstate Medical University, Syracuse, N.Y, USA.
Mol Neuropsychiatry. 2017 Feb;2(4):173-184. doi: 10.1159/000450726. Epub 2016 Oct 12.
To localize genetic variation affecting risk for psychotic disorders in the population of Palau, we genotyped DNA samples from 203 Palauan individuals diagnosed with psychotic disorders, broadly defined, and 125 control subjects using a genome-wide single nucleotide polymorphism array. Palau has unique features advantageous for this study: due to its population history, Palauans are substantially interrelated; affected individuals often, but not always, cluster in families; and we have essentially complete ascertainment of affected individuals. To localize risk variants to genomic regions, we evaluated long-shared haplotypes, ≥10 Mb, identifying clusters of affected individuals who share such haplotypes. This extensive sharing, typically identical by descent, was significantly greater in cases than population controls, even after controlling for relatedness. Several regions of the genome exhibited substantial excess of shared haplotypes for affected individuals, including 3p21, 3p12, 4q28, and 5q23-q31. Two of these regions, 4q28 and 5q23-q31, showed significant linkage by traditional LOD score analysis and could harbor variants of more sizeable risk for psychosis or a multiplicity of risk variants. The pattern of haplotype sharing in 4q28 highlights , encoding a cadherin-related neuronal receptor, as possibly involved in risk.
为了在帕劳人群中定位影响精神疾病风险的基因变异，我们使用全基因组单核苷酸多态性阵列对203名被诊断患有广义精神疾病的帕劳个体和125名对照受试者的DNA样本进行了基因分型。帕劳具有有利于本研究的独特特征：由于其人口历史，帕劳人之间有很大的亲缘关系；受影响的个体经常（但不总是）在家族中聚集；而且我们基本上能够完全确定受影响的个体。为了将风险变异定位到基因组区域，我们评估了长度≥10 Mb的长共享单倍型，识别出共享此类单倍型的受影响个体簇。即使在控制了亲缘关系之后，这种广泛的共享（通常是同源相同的）在病例中也明显多于群体对照。基因组的几个区域在受影响个体中表现出大量过量的共享单倍型，包括3p21、3p12、4q28和5q23 - q31。其中两个区域，4q28和5q23 - q31，通过传统的LOD评分分析显示出显著的连锁关系，可能含有对精神病风险更大的变异或多种风险变异。4q28中的单倍型共享模式突出了 ，其编码一种钙黏蛋白相关的神经元受体，可能与风险有关。
