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Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson's disease in Chinese population.

ABSTRACT: Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P_combined = 1.47 × 10^-9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P < 5 × 10^-8) for PD in Chinese population. Moreover, of the reported genome-wide significant risk variants found mostly in European ancestry populations, the correlation coefficient (r_b) of effect size accounting for sampling errors was 0.91 between datasets and 63.6% attained P < 0.05 in Chinese population. Accordingly, we estimated a heritability of 0.14-0.18 for PD, and a moderate genetic correlation between European ancestry and Chinese populations (r_g = 0.47, se = 0.21). Polygenic risk score (PRS) analysis revealed that individuals with PRS values in the highest quartile had a 3.9-fold higher risk of developing PD than the lowest quartile. In conclusion, the present GWAS identified PD-associated variants in Chinese population, as well as genetic factors shared among distant populations. Our findings shed light on the genetic homogeneity and heterogeneity of PD in different ethnic groups and suggested WGS might continue to improve our understanding of the genetic architecture of PD.

SUBMITTER: Pan H

PROVIDER: S-EPMC9911746 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson's disease in Chinese population.

Pan Hongxu H Liu Zhenhua Z Ma Jinghong J Li Yuanyuan Y Zhao Yuwen Y Zhou Xiaoxia X Xiang Yaqin Y Wang Yige Y Zhou Xun X He Runcheng R Xie Yali Y Zhou Qiao Q Yuan Kai K Xu Qian Q Sun Qiying Q Wang Junling J Yan Xinxiang X Zhang Hainan H Wang Chunyu C Lei Lifang L Liu Weiguo W Wang Xuejing X Ding Xuebing X Wang Tao T Xue Zheng Z Zhang Zhentao Z Chen Ling L Wang Qing Q Liu Yonghong Y Tang Jiayu J Zhang Xuewei X Peng Shifang S Wang Chaodong C Ding Jianqing J Liu Chunfeng C Wang Lijuan L Chen Haibo H Shen Lu L Jiang Hong H Wu Xinyin X Tan Hongzhuan H Luo Dan D Xiao Shuiyuan S Chen Xiang X Tan Jieqiong J Hu Zhengmao Z Chen Chao C Xia Kun K Zhang Zhuohua Z Foo Jia Nee JN Blauwendraat Cornelis C Nalls Mike A MA Singleton Andrew B AB Liu Jun J Chan Piu P Zheng Houfeng H Li Jinchen J Guo Jifeng J Yang Jian J Tang Beisha B

NPJ Parkinson's disease 20230209 1

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P<sub>combin ...[more]

PMID: 36759515

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Project description:BackgroundPulmonary hypertension (PH) is a rare disease characterized by proliferation and occlusion of small pulmonary arterioles, which has been associated with a high mortality rate. The pathogenesis of PH is complex and incompletely understood, which includes both genetic and environmental factors that alter vascular structure and function.MethodsThus we aimed to reveal the potential genetic etiology of PH by targeting 143 tag SNPs of 14 candidate genes. Totally 208 individuals from Chinese Han population were enrolled in the present study, including 109 non-idiopathic PH patients and 99 healthy controls.ResultsThe data revealed that 2 SNPs were associated with PH overall susceptibility at p < 3×10- 4 after Bonferroni correction. The top hit was rs6557421 (p = 4.5×10- 9), located within Nox3 gene on chromosome 6. Another SNP rs3744439 located in Tbx4 gene, also showed evidence of association with PH susceptibility (p = 1.2×10- 6). The distribution of genotype frequencies of rs6557421 and rs3744439 have dramatic differences between PH patients and controls. Individuals with rs6557421 TT genotype had a 10.72-fold/14.20-fold increased risk to develop PH when compared with GG or GG/GT carriers in codominant or recessive model, respectively (TT versus GG: 95%CI = 4.79-24.00; TT versus GG/GT: 95%CI = 6.65-30.33). As for rs3744439, AG genotype only occurred in healthy controls but has not been observed in PH patients. We further validated the result by using 26 different populations from five regions around the globe, including African (AFR), American (AMR), East Asian (EAS), European (EUR), and South Asian (SAS). In consistent with the present case-control study's results, significantly different genotype frequencies of the observed SNPs existed between PH patients and healthy individuals from all over the world.ConclusionsThe results suggested that rs6557421 variant in Nox3 and rs3744439 variant in Tbx4 might have potential effect on individual susceptibility to pulmonary hypertension, which could lead to therapeutic or diagnosis approaches in PH.

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Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson's disease in Chinese population.

Publications

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson's disease in Chinese population.

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