TY  - JOUR
AU  - Billingsley, Kimberley J
AU  - Ding, Jinhui
AU  - Jerez, Pilar Alvarez
AU  - Illarionova, Anastasia
AU  - Levine, Kristin
AU  - Grenn, Francis P
AU  - Makarious, Mary B
AU  - Moore, Anni
AU  - Vitale, Daniel
AU  - Reed, Xylena
AU  - Hernandez, Dena
AU  - Torkamani, Ali
AU  - Ryten, Mina
AU  - Hardy, John
AU  - Chia, Ruth
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  - Quinn, John P
AU  - Bubb, Vivien J
AU  - Collins, Ryan L
AU  - Zhao, Xuefang
AU  - Walker, Mark
AU  - Pierce-Hoffman, Emma
AU  - Brand, Harrison
AU  - Talkowski, Michael E
AU  - Casey, Bradford
AU  - Cookson, Mark R
AU  - Markham, Androo
AU  - Nalls, Mike A
AU  - Mahmoud, Medhat
AU  - Sedlazeck, Fritz J
AU  - Blauwendraat, Cornelis
AU  - Gibbs, J Raphael
AU  - Singleton, Andrew B
TI  - Genome-Wide Analysis of Structural Variants in Parkinson Disease.
JO  - Annals of neurology
VL  - 93
IS  - 5
SN  - 0364-5134
CY  - Hoboken, NJ
PB  - Wiley-Blackwell
M1  - DZNE-2023-00288
SP  - 1012-1022
PY  - 2023
N1  - CC BY-NC
AB  -  Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data.We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4.We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023;93:1012-1022.
KW  - Humans
KW  - Genome-Wide Association Study
KW  - Parkinson Disease: genetics
KW  - Genome, Human
KW  - Whole Genome Sequencing
KW  - Genotype
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10192042
C6  - pmid:36695634
DO  - DOI:10.1002/ana.26608
UR  - https://pub.dzne.de/record/255487
ER  -