中国人群非综合征型唇裂伴或不伴腭裂的单核苷酸多态性遗传度

doi:10.19723/j.issn.1671-167X.2024.05.004

摘要/Abstract

摘要：

目的: 探索非综合征型唇裂伴或不伴腭裂(non-syndromic cleft lip with or without cleft palate, NSCL/P)全基因组常见遗传变异对NSCL/P风险的影响。方法: 利用全基因组关联研究(genome-wide association study, GWAS)数据，以全基因组单核苷酸多态性(single nucleotide polymorphism, SNP)遗传度和基因组不同分区SNP遗传度评估基因组上常见变异的效应。对GWAS汇总数据进行质量控制，标准包括数据中无缺失值、弱势等位基因频率≥1%、P值在0~1、SNP正负链明确等。利用连锁不平衡得分回归计算NSCL/P的SNP遗传度，采用分层的连锁不平衡得分回归计算基因组编码区、启动子区、内含子区、增强子区和超级增强子区的分区SNP遗传度，并评估不同分区内的富集度，分析工具为LDSC (v1.0.1)软件。结果: 纳入中国人群806个NSCL/P核心家系(2 418人)的GWAS数据，490 593个SNP通过质量控制，被纳入到SNP遗传度的计算中。观测样本中NSCL/P的SNP遗传度为0.55(95%CI: 0.28~0.82), 由于观测样本患病率较高，按中国人群患病率转换为一般人群后SNP遗传度为0.37(95%CI: 0.19~0.55)。SNP遗传度在增强子区的富集度为15.70(P=0.04)，在超级增强子区的富集度为3.18(P=0.03)。结论: 基因组常见变异有助于解释一部分中国人群NSCL/P目前未被解释的遗传度，同时中国人群NSCL/P的SNP遗传度在增强子分区和超级增强子分区中显著富集，提示该区域中可能存在未被发现的遗传致病因素。

关键词: 非综合征型唇裂伴或不伴腭裂, 单核苷酸多态性遗传度, 核心家系

Abstract:

Objective: To delve into the intricate relationship between common genetic variations across the entire genome and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). Methods: Utilizing summary statistics data from genome-wide association studies (GWAS), a thorough investigation to evaluate the impact of common variations on the genome were undertook. This involved assessing single nucleotide polymorphism (SNP) heritability across the entire genome, as well as within specific genomic regions. To ensure the robustness of our analysis, stringent quality control measures were applied to the GWAS summary statistics data. Criteria for inclusion encompassed the absence of missing values, a minor allele frequency ≥1%, P-values falling within the range of 0 to 1, and clear SNP strand orientation. SNP meeting these stringent criteria were then meticulously included in our analysis. The SNP heritability of NSCL/P was calculated using linkage disequilibrium score regression. Additionally, hierarchical linkage disequilibrium score regression to partition SNP heritability within coding regions, promoters, introns, enhancers, and super enhancers were employed, and the enrichment levels within different genomic regions using LDSC (v1.0.1) software were further elucidated. Results: Our study drew upon GWAS summary statistics data obtained from 806 NSCL/P trios, comprising a total of 2 418 individuals from the Chinese population. Following rigorous quality control procedures, 490 593 out of 492 993 SNP were deemed suitable for inclusion in SNP heritability calculations. The observed SNP heritability of NSCL/P was 0.55 (95%CI: 0.28-0.82). Adjusting for the elevated disease pre-valence within our sample, the SNP heritability scaled down to 0.37 (95%CI: 0.19-0.55) based on the prevalence observed in the general Chinese population. Notably, our enrichment analysis unveiled significant enrichment of SNP heritability within enhancer regions (15.70, P=0.04) and super enhancer regions (3.18, P=0.03). Conclusion: Our study sheds light on the intricate interplay between common genetic variations and the risk of NSCL/P in the Chinese population. By elucidating the SNP heritability landscape across different genomic regions, we contribute valuable insights into the genetic basis of NSCL/P. The significant enrichment of SNP heritability within enhancer and super enhancer regions underscores the potential role of these regulatory elements in shaping the genetic susceptibility to NSCL/P. This paves the way for further research aimed at uncovering novel genetic pathogenic factors underlying NSCL/P pathogenesis.

Key words: Non-syndromic cleft lip with or without cleft palate, Single nucleotide polymorphism heritability, Case-parent trios

中图分类号:

R394.1

薛恩慈, 陈曦, 王雪珩, 王斯悦, 王梦莹, 李劲, 秦雪英, 武轶群, 李楠, 李静, 周治波, 朱洪平, 吴涛, 陈大方, 胡永华. 中国人群非综合征型唇裂伴或不伴腭裂的单核苷酸多态性遗传度[J]. 北京大学学报（医学版）, 2024, 56(5): 775-780.

Enci XUE, Xi CHEN, Xueheng WANG, Siyue WANG, Mengying WANG, Jin LI, Xueying QIN, Yiqun WU, Nan LI, Jing LI, Zhibo ZHOU, Hongping ZHU, Tao WU, Dafang CHEN, Yonghua HU. Single nucleotide polymorphism heritability of non-syndromic cleft lip with or without cleft palate in Chinese population[J]. Journal of Peking University (Health Sciences), 2024, 56(5): 775-780.

图/表 2

表1

表2

参考文献 38

1	Mossey PA , Little J , Munger RG , et al. Cleft lip and palate[J]. Lancet, 2009, 374 (9703): 1773- 1785. doi: 10.1016/S0140-6736(09)60695-4
2	Wang M , Yuan Y , Wang Z , et al. Prevalence of orofacial clefts among live births in China: A systematic review and meta-analysis[J]. Birth Defects Res, 2017, 109 (13): 1011- 1019. doi: 10.1002/bdr2.1043
3	Sivertsen A , Wilcox AJ , Skjaerven R , et al. Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives[J]. BMJ, 2008, 336 (7641): 432- 434. doi: 10.1136/bmj.39458.563611.AE
4	Grosen D , Bille C , Petersen I , et al. Risk of oral clefts in twins[J]. Epidemiology, 2011, 22 (3): 313- 319. doi: 10.1097/EDE.0b013e3182125f9c
5	Leslie EJ , Carlson JC , Shaffer JR , et al. Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate[J]. Am J Med Genet A, 2017, 173 (6): 1531- 1538. doi: 10.1002/ajmg.a.38210
6	Eichler EE , Flint J , Gibson G , et al. Missing heritability and strategies for finding the underlying causes of complex disease[J]. Nat Rev Genet, 2010, 11 (6): 446- 450. doi: 10.1038/nrg2809
7	Yang J , Zeng J , Goddard ME , et al. Concepts, estimation and interpretation of SNP-based heritability[J]. Nat Genet, 2017, 49 (9): 1304- 1310. doi: 10.1038/ng.3941
8	Eaves LJ , Last KA , Young PA , et al. Model-fitting approaches to the analysis of human behaviour[J]. Heredity (Edinb), 1978, 41 (3): 249- 320. doi: 10.1038/hdy.1978.101
9	Keller MC , Coventry WL . Quantifying and addressing parameter indeterminacy in the classical twin design[J]. Twin Res Hum Genet, 2005, 8 (3): 201- 213. doi: 10.1375/twin.8.3.201
10	Bulik-Sullivan BK , Loh PR , Finucane HK , et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies[J]. Nat Genet, 2015, 47 (3): 291- 295. doi: 10.1038/ng.3211
11	Zhu H , Zhou X . Statistical methods for SNP heritability estimation and partition: A review[J]. Comput Struct Biotechnol J, 2020, 18, 1557- 1568. doi: 10.1016/j.csbj.2020.06.011
12	Consortium GP . An integrated map of genetic variation from 1 092 human genomes[J]. Nature, 2012, 491 (7422): 56- 65. doi: 10.1038/nature11632
13	Kircher M , Witten DM , Jain P , et al. A general framework for estimating the relative pathogenicity of human genetic variants[J]. Nat Genet, 2014, 46 (3): 310- 315. doi: 10.1038/ng.2892
14	GTEx Consortium . Human genomics. The genotype-tissue expression (GTEx) pilot analysis: Multitissue gene regulation in humans[J]. Science, 2015, 348 (6235): 648- 660. doi: 10.1126/science.1262110
15	Roadmap Epigenomics Consortium . Integrative analysis of 111 reference human epigenomes[J]. Nature, 2015, 518 (7539): 317- 330. doi: 10.1038/nature14248
16	Won HH , Natarajan P , Dobbyn A , et al. Disproportionate contributions of select genomic compartments and cell types to genetic risk for coronary artery disease[J]. PLoS Genet, 2015, 11 (10): e1005622. doi: 10.1371/journal.pgen.1005622
17	Beaty TH , Murray JC , Marazita ML , et al. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4[J]. Nat Genet, 2010, 42 (6): 525- 529. doi: 10.1038/ng.580
18	Haeussler M , Zweig AS , Tyner C , et al. The UCSC genome browser database: 2019 update[J]. Nucleic Acids Res, 2019, 47 (D1): D853- D858. doi: 10.1093/nar/gky1095
19	Hoffman MM , Ernst J , Wilder SP , et al. Integrative annotation of chromatin elements from ENCODE data[J]. Nucleic Acids Res, 2013, 41 (2): 827- 841. doi: 10.1093/nar/gks1284
20	Hnisz D , Abraham BJ , Lee TI , et al. Super-enhancers in the control of cell identity and disease[J]. Cell, 2013, 155 (4): 934- 947. doi: 10.1016/j.cell.2013.09.053
21	Finucane HK , Bulik-Sullivan B , Gusev A , et al. Partitioning heritability by functional annotation using genome-wide association summary statistics[J]. Nat Genet, 2015, 47 (11): 1228- 1235. doi: 10.1038/ng.3404
22	Witte JS , Visscher PM , Wray NR . The contribution of genetic variants to disease depends on the ruler[J]. Nat Rev Genet, 2014, 15 (11): 765- 776. doi: 10.1038/nrg3786
23	Ludwig KU , Böhmer AC , Bowes J , et al. Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip ± cleft palate and cleft palate only[J]. Hum Mol Genet, 2017, 26 (4): 829- 842.
24	Wood AR , Esko T , Yang J , et al. Defining the role of common variation in the genomic and biological architecture of adult human height[J]. Nat Genet, 2014, 46 (11): 1173- 1186. doi: 10.1038/ng.3097
25	Locke AE , Kahali B , Berndt SI , et al. Genetic studies of body mass index yield new insights for obesity biology[J]. Nature, 2015, 518 (7538): 197- 206. doi: 10.1038/nature14177
26	Pantelis C , Papadimitriou GN , Papiol S , et al. Biological insights from 108 schizophrenia-associated genetic loci[J]. Nature, 2014, 511 (7510): 421- 427. doi: 10.1038/nature13595
27	Okada Y , Wu D , Trynka G , et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery[J]. Nature, 2014, 506 (7488): 376- 381. doi: 10.1038/nature12873
28	Liu JZ , van Sommeren S , Huang H , et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations[J]. Nat Genet, 2015, 47 (9): 979- 986. doi: 10.1038/ng.3359
29	Yu Y , Zuo X , He M , et al. Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity[J]. Nat Commun, 2017, 8, 14364. doi: 10.1038/ncomms14364
30	Suazo J , Recabarren AS , Marín NR , et al. Association between IRF6 variants and nonsyndromic cleft lip with or without cleft palate in Chile[J]. Reprod Sci, 2020, 27 (10): 1857- 1862. doi: 10.1007/s43032-020-00203-9
31	Zucchero TM , Cooper ME , Maher BS , et al. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate[J]. N Engl J Med, 2004, 351 (8): 769- 780. doi: 10.1056/NEJMoa032909
32	Rahimov F , Marazita ML , Visel A , et al. Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip[J]. Nat Genet, 2008, 40 (11): 1341- 1347. doi: 10.1038/ng.242
33	Morris VE , Hashmi SS , Zhu L , et al. Evidence for craniofacial enhancer variation underlying nonsyndromic cleft lip and palate[J]. Hum Genet, 2020, 139 (10): 1261- 1272. doi: 10.1007/s00439-020-02169-9
34	Whyte WA , Orlando DA , Hnisz D , et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes[J]. Cell, 2013, 153 (2): 307- 319. doi: 10.1016/j.cell.2013.03.035
35	Gröschel S , Sanders MA , Hoogenboezem R , et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia[J]. Cell, 2014, 157 (2): 369- 381. doi: 10.1016/j.cell.2014.02.019
36	Visel A , Minovitsky S , Dubchak I , et al. VISTA enhancer browser: A database of tissue-specific human enhancers[J]. Nucleic Acids Res, 2007, 35 (Database issue): D88- D92.
37	Gao T , Qian J . EnhancerAtlas 2.0: An updated resource with enhancer annotation in 586 tissue/cell types across nine species[J]. Nucleic Acids Res, 2020, 48 (D1): D58- D64.
38	Evans LM , Tahmasbi R , Vrieze SI , et al. Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits[J]. Nat Genet, 2018, 50 (5): 737- 745. doi: 10.1038/s41588-018-0108-x

Metrics

Viewed

Full text

Abstract

Cited

Shared

Discussed

Site	Male	Female	Total
China Taiwan, n	139	94	233
Shandong, n	193	81	274
Hubei, n	132	55	187
Sichuan, n	75	37	112
Total, n	539	267	806

Annotation	Proportion of SNP	Proportion of SNP heritability	Enrichment	P for enrichment
Coding	0.014	0.035	2.44	0.91
Promoter	0.046	0.144	3.12	0.70
Intron	0.388	0.289	0.74	0.63
Enhancer	0.042	0.654	15.70	0.04
Super-enhancer	0.167	0.532	3.18	0.03

[1]	侯天姣,周治波,王竹青,王梦莹,王斯悦,彭和香,郭煌达,李奕昕,章涵宇,秦雪英,武轶群,郑鸿尘,李静,吴涛,朱洪平. 转化生长因子β信号通路与非综合征型唇腭裂发病风险的基因-基因及基因-环境交互作用[J]. 北京大学学报（医学版）, 2024, 56(3): 384-389.
[2]	陈曦,王斯悦,薛恩慈,王雪珩,彭和香,范梦,王梦莹,武轶群,秦雪英,李劲,吴涛,朱洪平,李静,周治波,陈大方,胡永华. 基于核心家系全外显子组测序数据探索新生突变与非综合征型唇腭裂的关联[J]. 北京大学学报（医学版）, 2022, 54(3): 387-393.
[3]	周仁,郑鸿尘,李文咏,王梦莹,王斯悦,李楠,李静,周治波,吴涛,朱洪平. 利用二代测序数据探索SPRY基因家族与中国人群非综合征型唇腭裂的关联[J]. 北京大学学报（医学版）, 2019, 51(3): 564-570.