TY - JOUR
T1 - Large-scale rare variant burden testing in Parkinson's disease
AU - UK Brain Expression Consortium (UKBEC)
AU - Makarious, Mary B.
AU - Lake, Julie
AU - Pitz, Vanessa
AU - Fu, Allen Ye
AU - Guidubaldi, Joseph L.
AU - Solsberg, Caroline Warly
AU - Bandres-Ciga, Sara
AU - Leonard, Hampton L.
AU - Kim, Jonggeol Jeffrey
AU - Billingsley, Kimberley J.
AU - Grenn, Francis P.
AU - Jerez, Pilar Alvarez
AU - Alvarado, Chelsea X.
AU - Iwaki, Hirotaka
AU - Ta, Michael
AU - Vitale, Dan
AU - Hernandez, Dena
AU - Torkamani, Ali
AU - Ryten, Mina
AU - Hardy, John
AU - Scholz, Sonja W.
AU - Traynor, Bryan J.
AU - Dalgard, Clifton L.
AU - Ehrlich, Debra J.
AU - Tanaka, Toshiko
AU - Ferrucci, Luigi
AU - Beach, Thomas G.
AU - Serrano, Geidy E.
AU - Real, Raquel
AU - Morris, Huw R.
AU - Ding, Jinhui
AU - Gibbs, J. Raphael
AU - Singleton, Andrew B.
AU - Nalls, Mike A.
AU - Bhangale, Tushar
AU - Blauwendraat, Cornelis
N1 - Publisher Copyright:
© The Author(s) 2023.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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.
AB - 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.
KW - GBA1
KW - LRRK2
KW - Parkinson’s disease
KW - burden
KW - genetics
KW - rare variant
UR - http://www.scopus.com/inward/record.url?scp=85176495410&partnerID=8YFLogxK
U2 - 10.1093/brain/awad214
DO - 10.1093/brain/awad214
M3 - Article
C2 - 37348876
AN - SCOPUS:85176495410
SN - 0006-8950
VL - 146
SP - 4622
EP - 4632
JO - Brain
JF - Brain
IS - 11
ER -