Genome‐Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India

Abstract

Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease‐relevant monogenic genes, rare variants of significance, and polygenic risk‐associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies pathogenic/likely pathogenic variants in eight of the 90 individuals (8.8%). It includes large homozygous coding exon deletions in PRKN and SNV/InDels in VPS13C, PLA2G6, PINK1, SYNJ1, and GCH1. Eleven rare heterozygous GBA coding variants are also identified in 13 (14.4%) individuals. In 34 (56.6%) individuals, one or more variants of uncertain significance (VUS) in PD/PD‐relevant genes are observed. Though YOPD patients with a prioritized pathogenic variant show a low polygenic risk score (PRS), patients with prioritized VUS or no significant rare variants show an increased PRS odds ratio for PD. This study suggests that both significant rare variants and polygenic risk from common variants together may contribute to the genesis of PD. Further validation using a larger cohort of patients will confirm the interplay between monogenic and polygenic variants and their use in routine genetic PD diagnosis and risk assessment.

The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

“…Of these 674 subjects, genotype array data was generated on 659 subjects. WGS data was available for a pilot cohort of 92 subjects, as described previously 17 , and we generated WES data on 576 subjects. Control subjects were selected from available WGS from GAsPh2; a total of 1,376 subjects met criteria for ancestry matching ( Fig.…”

“…We combined WGS data from a pilot cohort of 92 subjects (previously described 17 ) with newly generated WES data for 576 additional individuals (Fig. S6) and assessed them for the presence of pathogenic, likely pathogenic, risk variants, or VUS in a list of 64 previously-associated PD genes by applying ACMG criteria (see Supporting Information Methods and Figs.…”

“…Variants were called with Sentieon’s GATK best practices germline pipeline and combined with results from WGS data for an additional 92 cases. Using American College of Medical Genetics (ACMG) criteria, we identified pathogenic, likely pathogenic, or variants of uncertain significance (VUS) in known PD genes in these 668 cases, as described previously (see Supporting Information Methods) 17 . For one identified variant in GBA1 , p.Ser164Arg, we compared levels and activity 37 of the corresponding enzyme β-Glucocerebrosidase (GCase) in homozygous variant knock-in (KI), GBA1 knock-out (KO), and wild-type (WT) A549 cells (see Supporting Information Methods).…”

“…In the present study, we address these limitations by conducting the largest genetic study of PD in a South Asian population to date, including genome-wide and case-control discovery approaches. Specifically, we jointly profiled 674 PD subjects predominantly with earlier onset PD from the Parkinson’s Research Alliance of India (PRAI) cohort via genotype array and whole exome sequencing (WES), expanding upon our previous study of 99 subjects from this cohort 17 . Combining these PD data with 1,376 ancestry-matched controls profiled via whole genome sequencing (WGS) and derived from a novel South Asian reference population 18,19 , we performed several studies quantifying variants and genes associated with PD diagnosis and age of onset, utilizing both common and rare variants.…”

“…However, South Asian populations remain particularly underrepresented in PD genetics studies 4 and in human genetics studies generally, comprising ~25% of the world population but only ~1% of individuals assessed overall in GWAS (as of 2018) 8 . Previous genetics studies of PD in South Asians have been limited by small sample size, a lack of genome-wide interrogation, and/or case-only analyses [9][10][11][12][13][14][15][16][17] . The success of recent efforts to broaden PD genetic discovery beyond European populations [5][6][7] , and the high rates of founder effects and consanguinity in South Asians (themselves imparting distinct advantages for variant and gene discovery) 18,19 render expanded genetics efforts in South Asians a promising opportunity to better understand the genetic basis of PD.…”