希腊人群隔离群体的基因特征揭示了错义变异和性状相关变异中的强烈基因漂变。

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核心技术专利：CN118964589B侵权必究

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核心技术专利：CN118964589B侵权必究

Panoutsopoulou Kalliope, Hatzikotoulas Konstantinos, Xifara Dionysia Kiara, Colonna Vincenza, Farmaki Aliki-Eleni, Ritchie Graham R S, Southam Lorraine, Gilly Arthur, Tachmazidou Ioanna, Fatumo Segun, Matchan Angela, Rayner Nigel W, Ntalla Ioanna, Mezzavilla Massimo, Chen Yuan, Kiagiadaki Chrysoula, Zengini Eleni, Mamakou Vasiliki, Athanasiadis Antonis, Giannakopoulou Margarita, Kariakli Vassiliki-Eirini, Nsubuga Rebecca N, Karabarinde Alex, Sandhu Manjinder, McVean Gil, Tyler-Smith Chris, Tsafantakis Emmanouil, Karaleftheri Maria, Xue Yali, Dedoussis George, Zeggini Eleftheria

Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.

1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK [2] Department of Statistics, University of Oxford, Oxford OX1 3TG, UK.

Nat Commun. 2014 Nov 6;5:5345. doi: 10.1038/ncomms6345.

Isolated populations are emerging as a powerful study design in the search for low-frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece and the Mylopotamos villages (HELIC-MANOLIS) in Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort, we observe an enrichment of missense variants among the variants that have drifted up in frequency by more than fivefold. In the Pomak cohort, we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example, with mean corpuscular volume (rs7116019, P=2.3 × 10(-26)). We replicate this association in a second set of Pomak samples (combined P=2.0 × 10(-36)). We demonstrate significant power gains in detecting medical trait associations.

在寻找与复杂表型相关的低频和罕见变异时，隔离群体正成为一种强大的研究设计。在此，我们对来自希腊两个隔离群体的2296个样本进行基因分型，这两个群体分别是希腊北部的波马克村庄（HELIC-Pomak）和克里特岛的米洛波塔莫斯村庄（HELIC-MANOLIS）。我们将它们的基因组特征与希腊普通人群进行比较，并将它们确立为遗传隔离群体。在MANOLIS队列中，我们观察到频率上升超过五倍的变异中错义变异有所富集。在波马克队列中，我们在11号染色体p15.4上的变异中发现了新的关联，这些变异的等位基因频率大幅增加（从希腊普通人群中的0.2%增加到隔离群体中的4.6%），与血液学特征相关，例如平均红细胞体积（rs7116019，P = 2.3×10^(-26)）。我们在第二组波马克样本中重复了这一关联（合并P = 2.0×10^(-36)）。我们证明了在检测医学性状关联方面有显著的效能提升。