| Title: | Large-scale rare variant burden testing in Parkinson's disease. |
| Journal: | Brain |
| Published: | 22 Jun 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37348876/ |
| DOI: | https://doi.org/10.1093/brain/awad214 |
| URL: | https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awad214/50682984/awad214.pdf |
Publication 7785
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Abstract
Parkinson's disease (PD) has a large heritable component and genome-wide association studies to date have identified over 90 loci with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for PD. To address this gap, we investigated the rare genetic component of PD at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7,184 PD cases, 6,701 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 PD, 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 in independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in PD. To date, this is the largest analysis of rare genetic variants in PD.48 Authors
- Mary B Makarious
- Julie Lake
- Vanessa Pitz
- Allen Ye Fu
- Joseph L Guidubaldi
- Caroline Warly Solsberg
- Sara Bandres-Ciga
- Hampton L Leonard
- Jonggeol Jeffrey Kim
- Kimberley J Billingsley
- Francis P Grenn
- Pilar Alvarez Jerez
- Chelsea Alvarado
- Hirotaka Iwaki
- Michael Ta
- Dan Vitale
- Dena Hernandez
- Ali Torkamani
- Mina Ryten
- John Hardy
- John Hardy
- Mike Weale
- Daniah Trabzuni
- Sebastian Guelfi
- Juan Botia
- Karishma D'Sa
- Paola Forabosco
- Colin Smith
- Adaikalavan Ramasamy
- Mina Ryten
- Regina H Reynolds
- Robert Walker
- Sonja W Scholz
- Bryan J Traynor
- Clifton L Dalgard
- Debra J Ehrlich
- Toshiko Tanaka
- Luigi Ferrucci
- Thomas G Beach
- Geidy E Serrano
- Raquel Real
- Huw R Morris
- Jinhui Ding
- J Raphael Gibbs
- Andrew B Singleton
- Mike A Nalls
- Tushar Bhangale
- Cornelis Blauwendraat
1 Application
| Application ID | Title |
|---|---|
| 33601 | Dissecting the genetic architecture of neurodegenerative diseases |
Enabling scientific discoveries that improve human health