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Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry.

ABSTRACT: BACKGROUND:Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80. METHODS:The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non-Ashkenazi Jewish LRRK2 p.G2019S carrier probands at 8 sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included when available. RESULTS:Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% confidence interval [CI]: 26.3%-65.8%) to age 80, which is not significantly higher than the previously estimated 25% (95% CI: 16.7%-34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the noncarrier relatives, as seen in Ashkenazi Jewish relatives. CONCLUSIONS:The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non-Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25% to 42.5% at age 80 in all populations analyzed. © 2017 International Parkinson and Movement Disorder Society.

SUBMITTER: Lee AJ

PROVIDER: S-EPMC5656509 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry.

Lee Annie J AJ Wang Yuanjia Y Alcalay Roy N RN Mejia-Santana Helen H Saunders-Pullman Rachel R Bressman Susan S Corvol Jean-Christophe JC Brice Alexis A Lesage Suzanne S Mangone Graziella G Tolosa Eduardo E Pont-Sunyer Claustre C Vilas Dolores D Schüle Birgitt B Kausar Farah F Foroud Tatiana T Berg Daniela D Brockmann Kathrin K Goldwurm Stefano S Siri Chiara C Asselta Rosanna R Ruiz-Martinez Javier J Mondragón Elisabet E Marras Connie C Ghate Taneera T Giladi Nir N Mirelman Anat A Marder Karen K

Movement disorders : official journal of the Movement Disorder Society 20170622 10

<h4>Background</h4>Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews an ...[more]

PMID: 28639421

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Project description:Abstract Population stratification, or systematic differences in allele frequencies between subpopulations, can distort the results from genome-wide association studies (GWAS). While GWAS are usually conducted within continental (e.g. European) ancestry groups, sub-groups may have specific population histories that result in enrichment for risk or protective alleles for complex disease. In this analysis, we examined genetic risk for glioma in a US population with predominantly Ashkenazi Jewish (AJ) ancestry. Genotyping data were obtained from three prior glioma case-control studies. Best-guess assignment to one of seven subcontinental European ancestry groups was performed using AIPS (https://github.com/biomedicaldatascience/AIPS). Out of a total of 6,416 cases and 7,441 controls across all three studies, 202 cases (3% of all cases, 63% GBM) and 403 controls (5% of all controls) were assigned to the AJ ancestry group. Unconditional logistic regression was performed for by study (adjusted for age and first two principal components) and then studies were combined using fixed effects meta-analysis. No associations reached genome-wide significance (p< 5x10-8), including those detected in prior pan-European GWAS. A nominally significant association was detected on chromosome 17 in ASPA (rs9904040, MAF=20%, p=2.61x10-6, Odds ratio=2.22 [95% confidence interval=1.59–3.09]) which is in linkage equilibrium (r2=0.0013) with the previously detected glioma risk SNP in TP53 (MAF=0.3% in this analysis, p=0.8801) in the European population. In our prior pan-European meta-analysis (Melin et al., 2017, this SNP was non-significant (p=0.0620). This study failed to replicate many previously identified glioma risk alleles, likely due to diminished power due to small sample size. We did identify a novel risk allele on chromosome 17 in ASPA, which encodes for aspartoacylase (which catalyzes deacylation of N-acetyl_L-aspartic acid). Larger sample sizes identified via targeted recruitment are necessary in order to fully characterize genetic risk for glioma in this population, including assessment of rare (MAF< 5%) risk allele associations.

Dataset Information

Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry.

Publications

Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry.

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