背景:来自代表性不足的祖先的大型生物库的基因组测序为在世界人口水平上询问孟德尔疾病负担提供了宝贵的资源,补充小规模家庭研究。
方法:这里,我们调查了来自卡塔尔的6045个全基因组,卡塔尔是一个在国家生物库登记的具有高血缘关系和未充分研究的突变负担的中东人群,并对58个临床相关数量性状进行了表型分析.我们检查了来自20个小组的2648个孟德尔基因,注释已知和新的致病变体,并评估其外显率和对测量性状的影响。
结果:我们发现62.5%的参与者是至少1种与隐性疾病有关的已知致病变异的携带者,在150名受试者中有1名(0.6%)观察到纯合性,其中半岛阿拉伯人相对于其他祖先特别富集(5.8倍)。平均而言,每个基因组发现了52.3个功能丧失变体,其中6.5影响已知的孟德尔基因。在ClinVar/HGMD中注释为致病性的几种变体在该队列中以中间频率出现(1-3%),强调阿拉伯创始人的影响,而其他人则有极高的频率(>5%)提示重新考虑为良性。此外,累积基因负荷分析显示,56个基因携带频率>1/50的基因,包括5个ACMGTier3组基因,这些基因将成为该国增加新生儿筛查的候选基因.此外,利用58个生物样本特征,我们系统地评估了新/罕见变异对表型的影响,并发现了39个与极端数量性状相关的候选大效应变异.此外,通过罕见的变体负担测试,我们发现了13个高突变负荷的基因,包括5个对疾病相关性状的影响,包括代谢紊乱和2型糖尿病,与该地区这些疾病的高患病率一致。
结论:这项关于卡塔尔基因组计划队列第一阶段的研究提供了来自中东人群的全面资源,以了解孟德尔基因的全球突变负担及其对看似健康的特征的影响在高血缘关系环境中的个体。
Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.
Here, we interrogate 6045 whole genomes from Qatar-a Middle Eastern population with high consanguinity and understudied mutational burden-enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits.
We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1-3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region.
This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.