Search

Additional file 1. Table S1. Characteristics of the Mayo cohort. Table S2. Characteristics of the MSBB cohort. Table S3. Detailed results from the univariate regression analyses shown in Fig. 2A. Table S4. Association between cell type proportions and mtDNAcn in the DLPFC. Table S5. Association between number of mtDNA heteroplasmic mutations and age adjusted for pathologic diagnosis. Table S6. Datasets and analysis results deposited at the AD Knowledge Portal. Fig. S1. Log-transformed mtDNAcn values are approximately normally distributed. Fig. S2. Changes of the mtDNAcn are primarily associated with tau in the DLPFC. Fig. S3. Significant fraction of the APOE ��4 effect on mtDNAcn is mediated via AD pathologies. Fig. S4. Number of mtDNA heteroplasmic mutations in cortical regions is associated with age adjusted for sex, pathologic diagnosis, and mtDNAcn. Fig. S5. Mitochondrial content score and its relation to mtDNAcn, mtDNA heteroplasmy burden and AD-related phenotypes.

In genetic epidemiological studies, family history data are collected on relatives of study participants and used to estimate the age-specific risk of disease for individuals who carry a causal mutation. However, a family member's genotype data may not be collected due to the high cost of in-person interview to obtain blood sample or death of a relative. Previously, efficient nonparametric genotype-specific risk estimation in censored mixture data has been proposed without considering covariates. With multiple predictive risk factors available, risk estimation requires a multivariate model to account for additional covariates that may affect disease risk simultaneously. Therefore, it is important to consider the role of covariates in the genotype-specific distribution estimation using family history data. We propose an estimation method that permits more precise risk prediction by controlling for individual characteristics and incorporating interaction effects with missing genotypes in relatives, and thus gene-gene interactions and gene-environment interactions can be handled within the framework of a single model. We examine performance of the proposed methods by simulations and apply them to estimate the age-specific cumulative risk of Parkinson's disease (PD) in carriers of LRRK2 G2019S mutation using first-degree relatives who are at genetic risk for PD. The utility of estimated carrier risk is demonstrated through designing a future clinical trial under various assumptions. Such sample size estimation is seen in the Huntington's disease literature using the length of abnormal expansion of a CAG repeat in the HTT gene, but is less common in the PD literature., 16 pages, 5 tables, 4 figures (7 Supplementary pages, 4 Supplementary tables, 13 Supplementary figures)

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.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.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.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.