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

被引：21

作者：

Makarious, Mary B. ^{[1
,2
,3
]}

Lake, Julie ^{[1
]}

Pitz, Vanessa ^{[4
]}

Fu, Allen Ye ^{[1
,5
]}

Guidubaldi, Joseph L. ^{[4
,6
,7
]}

Solsberg, Caroline Warly ^{[8
,9
]}

Bandres-Ciga, Sara ^{[6
,7
]}

Leonard, Hampton L. ^{[1
,6
,7
,10
]}

Kim, Jonggeol Jeffrey ^{[4
,11
]}

Billingsley, Kimberley J. ^{[1
,6
,7
]}

Grenn, Francis P. ^{[1
]}

Jerez, Pilar Alvarez ^{[1
,6
,7
]}

Alvarado, Chelsea X. ^{[6
,7
,10
]}

Iwaki, Hirotaka ^{[1
,6
,7
,10
]}

Ta, Michael ^{[6
,7
,10
]}

Vitale, Dan ^{[6
,7
,10
]}

Hernandez, Dena ^{[1
]}

Torkamani, Ali ^{[12
]}

Ryten, Mina ^{[13
,14
]}

Hardy, John ^{[15
,16
,17
,18
,19
]}

Scholz, Sonja W. ^{[20
,21
]}

Traynor, Bryan J. ^{[1
,21
]}

Dalgard, Clifton L. ^{[22
]}

Ehrlich, Debra J. ^{[23
]}

Tanaka, Toshiko ^{[24
]}

Ferrucci, Luigi ^{[24
]}

Beach, Thomas G. ^{[25
]}

Serrano, Geidy E. ^{[25
]}

Real, Raquel ^{[2
,3
]}

Morris, Huw R. ^{[2
,3
]}

Ding, Jinhui ^{[1
]}

Gibbs, J. Raphael ^{[1
]}

Singleton, Andrew B. ^{[1
,6
,7
]}

Nalls, Mike A. ^{[1
,6
,7
]}

Bhangale, Tushar ^{[26
]}

Blauwendraat, Cornelis ^{[1
,4
,7
]}

机构：

[1] NIA, Lab Neurogenet, NIH, Bethesda, MD 20814 USA

[2] UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, London WC1N 3BG, England

[3] UCL, UCL Movement Disorders Ctr, London WC1N 3BG, England

[4] NIA, Integrat Neurogenom Unit, Lab Neurogenet, NIH, Bethesda, MD 20814 USA

[5] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA

[6] NIA, Ctr Alzheimers & Related Dementias CARD, NIH, Bethesda, MD 20814 USA

[7] NINDS, NIH, Bethesda, MD 20814 USA

[8] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94158 USA

[9] Univ Calif San Francisco, Pharmaceut Sci & Pharmacogen, San Francisco, CA 94143 USA

[10] Data Tecn Int, Washington, DC 20812 USA

[11] Queen Mary Univ London, Wolfson Inst Prevent Med, Prevent Neurol Unit, London EC1M 6BQ, England

[12] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[13] UCL, NIHR Great Ormond St Hosp Biomed Res Ctr, London WC1N 1EH, England

[14] UCL, Great Ormond St Inst Child Hlth, Dept Genet & Genom Med, London WC1N 1EH, England

[15] UCL, UK Dementia Res Inst, London WC1N 3BG, England

[16] UCL, Dept Neurodegenerat Dis, UCL Queen Sq Inst Neurol, London WC1N 3BG, England

[17] UCL, Reta Lila Weston Inst, UCL Queen Sq Inst Neurol, London WC1N 3BG, England

[18] UCL, UCL Movement Disorders Ctr, London WC1N 3BG, England

[19] Hong Kong Univ Sci & Technol, Inst Adv Study, Hong Kong, Peoples R China

[20] NINDS, Neurodegenerat Dis Res Unit, Bethesda, MD 20814 USA

[21] Johns Hopkins Univ, Med Ctr, Dept Neurol, Baltimore, MD 21287 USA

[22] Uniformed Serv Univ Hlth Sci, Amer Genome Ctr, Bethesda, MD 20814 USA

[23] NINDS, Parkinsons Dis Clin, Off Clin Director, Bethesda, MD 20814 USA

[24] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA

[25] Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ 85351 USA

[26] Genentech Inc, Dept Human Genet, South San Francisco, CA 94080 USA

来源：

BRAIN | 2023年 / 146卷 / 11期

基金：

美国国家卫生研究院;

关键词：

Parkinson's disease; burden; GBA1; LRRK2; genetics; rare variant; PARKINSONS-DISEASE; ASSOCIATION ANALYSIS; GENOME; MUTATION; RISK; IDENTIFICATION; METAANALYSIS; INCREASES; FRAMEWORK; SINGLE;

D O I：

10.1093/brain/awad214

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：4622 / 4632

页数：11

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