Hum Mol Genet. 2022 Feb 3;31(3):347-361. doi: 10.1093/hmg/ddab252.
Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.
血小板在血栓形成和止血中起着关键作用。血小板计数（PLT）和平均血小板体积（MPV）是高度遗传的数量性状，以前已经鉴定出数百个遗传信号，这些信号主要在欧洲血统人群中发现。我们在这里利用 NHLBI 的 Trans-Omics for Precision Medicine 倡议（TOPMed）的全基因组测序（WGS）在一个大型多民族样本中进一步探索常见和罕见变异对 PLT（n=61,200）和 MPV（n=23,485）的贡献。我们在 MPL（rs532784633）和 PECAM1（rs73345162）中鉴定并复制了次要信号，这些信号在非洲裔人群中更为常见。我们还观察到 Mendelian 血小板相关疾病基因中的罕见变异会影响 TOPMed 队列中的血小板特征变异（未富集血液疾病）。例如，GP9 与较低的 PLT 和较高的 MPV 相关的原因部分是由伯纳德-苏利综合征的致病性变异（rs5030764，p.Asn61Ser）驱动，而 TUBB1 和 CD36 中的信号部分是由 ClinVar 中未注释为致病性的失活变异（rs199948010 和 rs571975065）驱动。然而，在调整了先导变异后，这些基于基因的信号仍然存在，这表明在一般人群队列中具有影响的 Mendelian 基因中的其他变异仍有待确定。在几个全基因组关联研究确定的基因座中也鉴定到了基于基因的信号，这些基因座未被注释为 Mendelian 血小板疾病基因（PTPRH、TET2、CHEK2），其中体细胞变异导致了 TET2 的结果。这些结果突出了 WGS 在遗传背景多样化的人群中识别新的调节和编码信号的价值，即使是血小板等研究充分的特征也是如此。
