Coding and Noncoding Variation in <scp><i>LRRK2</i></scp> and Parkinson's Disease Risk

Lake, Julie; Reed, Xylena; Langston, Rebekah G.; Nalls, Mike A.; Gan‐Or, Ziv; Cookson, Mark; Singleton, Andrew B.; Blauwendraat, Cornelis; Leonard, Hampton

doi:10.1002/mds.28787

Cited by 22 publications

(15 citation statements)

References 54 publications

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“…Multiple independent risk variants were identified by GWASs in the LRRK2 region of European ancestry populations 8,28 , and this observation was confirmed in Chinese with LRRK2-A419V, LRRK2-G2385R, and LRRK2-R1628P showing associations independently. However, the risk variants of LRRK2 exhibited significantly different incidence across populations.…”

Section: Discussionmentioning

confidence: 79%

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

Pan

et al. 2023

npj Parkinsons Dis.

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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 (Pcombined = 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 (rb) 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 (rg = 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.

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Section: Discussionmentioning

confidence: 79%

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

Pan

et al. 2023

npj Parkinsons Dis.

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“…Apart from that, the possibility that it is not necessarily the diagnosis of IBD but rather an associated inflammatory mediator that is associated with the risk of PD could not be ruled out with our MR study. A prior study showed that both rare and common variations at the leucine-rich repeat kinase 2 ( LRRK2 ) gene can influence PD susceptibility 18 , 19 . However, rare coding variants are not captured by GWAS studies.…”

Section: Discussionmentioning

confidence: 99%

Association between inflammatory bowel disease and Parkinson’s disease: A Mendelian randomization study

Freuer

Meisinger

2022

npj Parkinsons Dis.

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Emerging evidence from observational studies suggests an increased risk of Parkinson’s disease (PD) in patients with inflammatory bowel disease (IBD). However, to date it is not clear whether a causal relationship exists. To investigate whether IBD is causally related to PD, a two-sample Mendelian randomization study was carried out. Independent genetic instruments from the largest available genome-wide association study (GWAS) for IBD (7045 cases, 456,327 controls) including European participants were used to investigate the association with PD (56,306 cases; 1.4 million controls). The results were validated by using a second IBD sample (12,882 cases; 21,770 controls) including the main subtypes ulcerative colitis (UC; 6968 cases; 20,464 controls) and Crohn’s disease (CD; 5956 cases; 14,927 controls). The radial inverse-variance weighted (IVW) approach was used in the primary analysis, and the robustness of the findings were confirmed in a number of sensitivity analyses. Finally, the recently proposed CAUSE approach was performed. There was no evidence of an association between IBD and PD (ORIVW = 0.98; 95% CI: [0.93; 1.04]; P = 0.48). This finding could be validated using a second sample of IBD cases (ORIVW = 0.98; 95% CI: [0.95; 1.02]; P = 0.36). Furthermore, MR analyses did not support a causal effect of CD (ORIVW = 1.00; 95% CI: [0.98; 1.03]; P = 0.96) or UC (ORIVW = 1.02; 95% CI: [0.98; 1.06]; P = 0.45) on PD. The present study suggests that neither IBD nor its subtypes CD and UC causally affect Parkinson’s disease in the European population. Further research is necessary to investigate whether intestinal inflammation impacts the development of PD.

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“…Among the pathogenic (ie, Mendelian) LRRK2 variants, G2019S reigns king in Western PD populations with respect to combined effect size in disease risk and higher frequency as affirmed by whole‐genome sequencing efforts globally 22 . In the United States alone, more than 5000 people with PD are estimated to be G2019S carriers 22,23 . This sizable population suggests a sufficient global population to support concurrent therapeutic candidate efficacy studies, though their efficiency will benefit greatly from mounting efforts to introduce routine CLIA‐certified (Clinical Laboratory Improvement Amendments) PD gene testing into the clinic.…”

Section: Figurementioning

confidence: 99%

“…22 In the United States alone, more than 5000 people with PD are estimated to be G2019S carriers. 22,23 This sizable population suggests a sufficient global population to support concurrent therapeutic candidate efficacy studies, though their efficiency will benefit greatly from mounting efforts to introduce routine CLIA-certified (Clinical Laboratory Improvement Amendments) PD gene testing into the clinic. Moreover, there are other opportunities besides Mendelian LRRK2 variant carriers (eg, G2019S-LRRK2 carriers) to garner the apparent benefits genetic targets provide for drug approval likelihood.…”

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confidence: 99%