Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans.
Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans.
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DOI：
10.1093/hmg/ddab088
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发表时间：
2021-07-28
影响因子：
3.5
通讯作者：
Newton R
中科院分区：
文献类型：
--
作者：
Fatumo S;Chikowore T;Kalyesubula R;Nsubuga RN;Asiki G;Nashiru O;Seeley J;Crampin AC;Nitsch D;Smeeth L;Kaleebu P;Burgess S;Nyirenda M;Franceschini N;Morris AP;Tomlinson L;Newton R
肾功能的全基因组关联研究（GWAS）已经发现了数百个位点，主要是在欧洲血统的人群中。我们进行了非洲大陆第一次估计肾小球滤过率（eGFR）的GWAS，eGFR是一种用于定义慢性肾脏疾病（CKD）的肾功能指标。我们对来自乌干达普通人群队列（GPC）的3288名东非人进行了eGFR的GWAS，并在来自妇女健康倡议的8224名非洲裔美国人中进行了复制。获得全基因组显著关联证据（P < 5 × 10−8）的基因座随后进行贝叶斯精细定位，以定位潜在的因果变异。在乌干达GPC中评价了根据先前报告的跨血统eGFR前导单核苷酸多态性（SNP）构建的遗传风险评分（GRS）的预测能力。我们确定并验证了两个eGFR位点。在甘氨酸脒基转移酶（GATM）位点，乌干达GPC GWAS中的关联信号（前导SNP rs2433603，P = 1.0 × 10−8）与先前报道的该位点的信号不同。在血红蛋白β（HBB）基因座，关联信号（前导SNP rs141845179，P = 3.0 × 10−8）先前已有报道。HBB位点的前导SNP占精细定位后因果关系后验概率的88%，但与肾脏表达数量性状位点不共定位。eGFR的跨血统GRS对乌干达人群没有显着预测性。在非洲大陆eGFR的第一个GWAS中，我们验证了GATM和HBB的两个先前报道的位点。在GATM位点，关联信号与先前报道的不同。这些结果证明了在非洲大陆进行GWAS的价值，为更大的财团提供了丰富的基因组资源，用于进一步发现和精细定位。该研究强调，在非洲进行额外的大规模努力是必要的，以进一步了解CKD的遗传结构。
Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women’s Health Initiative. Loci attaining genome-wide significant evidence for association (P < 5 × 10−8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10−8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10−8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.
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影响因子：
64.8
作者：
Gurdasani, Deepti;Carstensen, Tommy;Tekola-Ayele, Fasil;Pagani, Luca;Tachmazidou, Ioanna;Hatzikotoulas, Konstantinos;Karthikeyan, Savita;Iles, Louise;Pollard, Martin O.;Choudhury, Ananyo;Ritchie, GrahamR. S.;Xue, Yali;Asimit, Jennifer;Nsubuga, Rebecca N.;Young, Elizabeth H.;Pomilla, Cristina;Kivinen, Katja;Rockett, Kirk;Kamali, Anatoli;Doumatey, Ayo P.;Asiki, Gershim;Seeley, Janet;Sisay-Joof, Fatoumatta;Jallow, Muminatou;Tollman, Stephen;Mekonnen, Ephrem;Ekong, Rosemary;Oljira, Tamiru;Bradman, Neil;Bojang, Kalifa;Ramsay, Michele;Adeyemo, Adebowale;Bekele, Endashaw;Motala, Ayesha;Norris, Shane A.;Pirie, Fraser;Kaleebu, Pontiano;Kwiatkowski, Dominic;Tyler-Smith, Chris;Rotimi, Charles;Zeggini, Eleftheria;Sandhu, Manjinder S.
通讯作者：
Sandhu, Manjinder S.
DOI：
10.1126/science.1193032
发表时间：
2010-08-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Genovese G;Friedman DJ;Ross MD;Lecordier L;Uzureau P;Freedman BI;Bowden DW;Langefeld CD;Oleksyk TK;Uscinski Knob AL;Bernhardy AJ;Hicks PJ;Nelson GW;Vanhollebeke B;Winkler CA;Kopp JB;Pays E;Pollak MR
通讯作者：
Pollak MR
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
2.9
作者：
McDonald HI;Thomas SL;Nitsch D
通讯作者：
Nitsch D
影响因子：
64.5
作者：
Gurdasani, Deepti;Carstensen, Tommy;Sandhu, Manj S.
通讯作者：
Sandhu, Manj S.