Large-scale rare variant burden testing in Parkinson's disease

• Published in: Brain (London, England : 1878) Vol. 146; no. 11; pp. 4622 - 4632
• Main Authors: Makarious, Mary B, Lake, Julie, Pitz, Vanessa, Ye Fu, Allen, Guidubaldi, Joseph L, Solsberg, Caroline Warly, Bandres-Ciga, Sara, Leonard, Hampton L, Kim, Jonggeol Jeffrey, Billingsley, Kimberley J, Grenn, Francis P, Jerez, Pilar Alvarez, Alvarado, Chelsea X, Iwaki, Hirotaka, Ta, Michael, Vitale, Dan, Hernandez, Dena, Torkamani, Ali, Ryten, Mina, Hardy, John, Scholz, Sonja W, Traynor, Bryan J, Dalgard, Clifton L, Ehrlich, Debra J, Tanaka, Toshiko, Ferrucci, Luigi, Beach, Thomas G, Serrano, Geidy E, Real, Raquel, Morris, Huw R, Ding, Jinhui, Gibbs, J Raphael, Singleton, Andrew B, Nalls, Mike A, Bhangale, Tushar, Blauwendraat, Cornelis
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 02.11.2023
• Subjects: Gene Frequency; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study - methods; Humans; Original; Parkinson Disease - genetics; Receptors, Immunologic; Risk Factors; genetics; rare variant; Parkinson’s disease; burden; GBA1; LRRK2
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awad214

Abstract Parkinson’s disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson’s disease. To address this gap, we investigated the rare genetic component of Parkinson’s disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson’s disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson’s disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson’s disease. To date, this is the largest analysis of rare genetic variants in Parkinson’s disease. Makarious et al. investigate the contribution of rare genetic variants, with minor allele frequencies <1%, to Parkinson’s disease risk. They confirm the known associations between rare variants in GBA1 and LRRK2 and Parkinson’s disease risk in individuals of European ancestry, and identify additional novel risk associations.