中国人群肝功能检测指标全基因组关联分析研究

doi:10.16288/j.yczz.20-435

遗传 ›› 2021, Vol. 43 ›› Issue (3): 249-260.doi: 10.16288/j.yczz.20-435

中国人群肝功能检测指标全基因组关联分析研究

孙一丹¹(), 田子钊¹, 周伟¹, 李沫¹, 怀聪¹, 贺林¹, 秦胜营¹()

¹ 上海交通大学Bio-X研究院,上海 200030

收稿日期:2020-12-16 出版日期:2021-03-16 发布日期:2021-03-03
基金资助:
国家自然科学基金项目(81773818);国家自然科学基金项目(82003856)

Genome-wide association study on liver function tests in Chinese

Yidan Sun¹(), Zizhao Tian¹, Wei Zhou¹, Mo Li¹, Cong Huai¹, Lin He¹, Shengying Qin¹()

¹ Bio-X Institute, Shanghai Jiaotong University, Shanghai 200030, China

Received:2020-12-16 Online:2021-03-16 Published:2021-03-03
Supported by:
the National Nature Science Foundation of China(81773818);the National Nature Science Foundation of China(82003856)

摘要/Abstract

摘要：

肝功能检测(liver function test, LFTs)指标是受遗传和环境影响的复杂性状,具有个体差异性。为系统性研究中国人群全基因组范围内单核苷酸多态性(single nucleotide polymorphism, SNP)与肝功能指标之间的联系,本研究利用英国生物银行(UK Biobank)中1653名中国人的基因分型数据和表型数据为研究对象,利用PLINK软件进行全关联分析研究(genome-wide association study, GWAS),发现229个SNP与中国人群血液中的总胆红素(total bilirubin, TB)相关,27个SNP与中国人群血液中碱性磷酸酶(alkaline phosphatase, ALP)相关,36个SNP与中国人群血液中的γ-谷氨酰转肽酶(γ-glutamyl transpeptidase, GGT)相关,1个SNP与中国人群血液中的门冬氨酸氨基转移酶(aspartate transaminase, AST)相关,最显著的位点中有11个位点是新的LFTs关联位点。通过功能基因组分析,发现这些位点的临床意义(如吉尔伯特综合征),确定了候选基因(UGT1A, ABO, GGT1),为从遗传角度理解中国人群LFTs的个体差异性和肝功能指标临床精准检测提供了前期研究基础。

关键词: 肝功能检测, 总胆红素, 碱性磷酸酶, γ-谷氨酰转肽酶, 全基因组关联分析

Abstract:

Liver function tests (LFTs) measure a series of complex traits that are affected by genetic and environmental factors. Previous studies demonstrated that there exist significant differences in LFTs across individuals, which may be the results of the unique genetic profile of each individual. Therefore, we performed a genome-wide association study (GWAS) to evaluate the influence of single nucleotide polymorphisms (SNPs) in LFTs and identify the significant association between genotypes and phenotypes using 1653 Chinese subjects from the UK Biobank database. We successfully identified 229 SNPs significantly associated with total bilirubin (TB) levels, 27 SNPs significantly associated with alkaline phosphatase (ALP), and 36 SNPs significantly associated with γ-glutamyl transpeptidase (GGT) in serum. In addition, one SNP significantly associated with aspartate transaminase (AST) in serum was also found. Among the most significant ones, the topmost 11 SNPs were found to be associated with LFTs for the first time. Through functional genomic analysis, the clinical significance of these SNPs could be associated with diseases (e.g. Gilbert's syndrome) and the respective candidate genes (UGT1A, ABO, GGT1). This study provides a preliminary rationale for research to understand the associations of individual genetic differences and clinical liver functions in the Chinese population.

Key words: Liver function tests, total bilirubin, alkaline phosphatase, γ-glutamyl transpeptidase, genome-wide association study

孙一丹, 田子钊, 周伟, 李沫, 怀聪, 贺林, 秦胜营. 中国人群肝功能检测指标全基因组关联分析研究[J]. 遗传, 2021, 43(3): 249-260.

Yidan Sun, Zizhao Tian, Wei Zhou, Mo Li, Cong Huai, Lin He, Shengying Qin. Genome-wide association study on liver function tests in Chinese[J]. Hereditas(Beijing), 2021, 43(3): 249-260.

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表型	染色体	位置	SNP编号	Ref/Alt	基因	所在区域	临床意义
TB	2	234665659	rs4124874	T/G	UGT1A3	内含子	吉尔伯特综合征
					UGT1A4	内含子
					UGT1A5	内含子
					UGT1A6	内含子
					UGT1A7	内含子
					UGT1A8	内含子
					UGT1A9	内含子
					UGT1A10	内含子
	2	234668570	rs887829	C/T	UGT1A1	上游	药物反应
					UGT1A3	内含子
					UGT1A4	内含子
					UGT1A5	内含子
					UGT1A6	内含子
					UGT1A7	内含子
					UGT1A8	内含子
					UGT1A9	内含子
					UGT1A10	内含子
	2	234669144	rs4148323	G/A	UGT1A1	错义	血清胆红素水平;吉尔伯特综合征;Lucey-Driscoll综合征;Crigler-Najjar综合征;药物反应
					UGT1A3	内含子
					UGT1A4	内含子
					UGT1A5	内含子
					UGT1A6	内含子
					UGT1A7	内含子
					UGT1A8	内含子
					UGT1A9	内含子
					UGT1A10	内含子
	2	234669619	rs35350960	C/A	UGT1A1	错义	吉尔伯特综合征;Crigler-Najjar综合征
					UGT1A3	内含子
					UGT1A4	内含子
					UGT1A5	内含子
					UGT1A6	内含子
					UGT1A7	内含子
					UGT1A8	内含子
					UGT1A9	内含子
					UGT1A10	内含子
ALP	9	136131651	rs1053878	G/A	ABO	错义	血型相关

表型	染色体	位置	SNP编号	Ref/Alt	评分	基因	所在区域
TB	2	234537447	rs13394704	G/T	1	UGT1A8	内含子
	2	234552292	rs1121395	G/A	0.97575	UGT1A8	内含子
	2	234552292	rs1121395	G/A	0.97575	UGT1A10	内含子
	2	234597483	rs11680450	T/C	0.97575	UGT1A7	内含子
						UGT1A8	内含子
						UGT1A9	内含子
						UGT1A10	内含子
	2	234548576	rs2018609	T/C	0.97501	UGT1A8	内含子
	2	234548576	rs2018609	T/C	0.97501	UGT1A10	内含子
	2	234582051	rs2602376	C/T	0.96333	UGT1A8	内含子
						UGT1A9	内含子
						UGT1A10	内含子
	2	234638690	rs2361501	A/T	0.9531	UGT1A3	内含子
						UGT1A4	内含子
						UGT1A5	内含子
						UGT1A6	内含子
						UGT1A7	内含子
						UGT1A8	内含子
						UGT1A9	内含子
						UGT1A10	内含子
	2	234593931	rs4338954	C/G	0.86817	UGT1A7	内含子
						UGT1A8	内含子
						UGT1A9	内含子
						UGT1A10	内含子
	2	234652347	rs13009407	C/G	0.83588	DNAJB3	同义突变
						UGT1A3	内含子
						UGT1A4	内含子
						UGT1A5	内含子
						UGT1A6	内含子
						UGT1A7	内含子
						UGT1A8	内含子
						UGT1A9	内含子
						UGT1A10	内含子
	2	234625622	rs1875263	C/T	0.82144	UGT1A4	内含子
						UGT1A5	内含子
						UGT1A6	内含子
						UGT1A7	内含子
						UGT1A8	内含子
						UGT1A9	内含子
						UGT1A10	内含子

表型	染色体	位置	SNP编号	Ref/Alt	评分	基因	所在区域
TB	2	234650604	rs4663965	T/C	0.82144	UGT1A3	内含子
						UGT1A4	内含子
						UGT1A5	内含子
						UGT1A6	内含子
						UGT1A7	内含子
						UGT1A8	内含子
						UGT1A9	内含子
						UGT1A10	内含子
ALP	9	136146597	rs550057	C/T	0.99	ABO	内含子
	9	136149830	rs532436	G/A	0.85537	ABO	内含子
	9	136151806	rs600038	T/C	0.82517	ABO	上游
GGT	22	24999104	rs2073398	C/G	0.93	GGT1	内含子
	22	24995663	rs2003757	C/T	0.86817	GGT1	内含子
	22	25000229	rs5751904	A/T	0.84289	GGT1	内含子

中国人群肝功能检测指标全基因组关联分析研究

Genome-wide association study on liver function tests in Chinese

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