TY - JOUR
T1 - The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease
AU - The International Parkinson's Disease Genomics Consortium (IPDGC)
AU - Bandres-Ciga, Sara
AU - Saez-Atienzar, Sara
AU - Bonet-Ponce, Luis
AU - Billingsley, Kimberley
AU - Vitale, Dan
AU - Blauwendraat, Cornelis
AU - Gibbs, Jesse Raphael
AU - Pihlstrøm, Lasse
AU - Gan-Or, Ziv
AU - Noyce, Alastair J.
AU - Kaiyrzhanov, Rauan
AU - Middlehurst, Ben
AU - Kia, Demis A.
AU - Tan, Manuela
AU - Houlden, Henry
AU - Morris, Huw R.
AU - Plun-Favreau, Helene
AU - Holmans, Peter
AU - Hardy, John
AU - Trabzuni, Daniah
AU - Bras, Jose
AU - Quinn, John
AU - Mok, Kin Y.
AU - Kinghorn, Kerri J.
AU - Wood, Nicholas W.
AU - Lewis, Patrick
AU - Schreglmann, Sebastian
AU - Guerreiro, Rita
AU - Lovering, Ruth
AU - RņBibo, Lea
AU - Rizig, Mie
AU - Ryten, Mina
AU - Guelfi, Sebastian
AU - Escott-Price, Valentina
AU - Chelban, Viorica
AU - Williams, Nigel
AU - Morrison, Karen E.
AU - Brice, Alexis
AU - Danjou, Fabrice
AU - Lesage, Suzanne
AU - Corvol, Jean Christophe
AU - Martinez, Maria
AU - Schulte, Claudia
AU - Brockmann, Kathrin
AU - SimɃn-Sȥnchez, Javier
AU - Heutink, Peter
AU - Rizzu, Patrizia
AU - Sharma, Manu
AU - Alcalay, Roy N.
AU - Hassin-Baer, Sharon
N1 - Publisher Copyright:
© 2019 International Parkinson and Movement Disorder Society
PY - 2019/4/1
Y1 - 2019/4/1
N2 - Background: PD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed. Objectives: To comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD. Methods: Linkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci. Results: The heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk. Conclusions: We provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions.
AB - Background: PD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed. Objectives: To comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD. Methods: Linkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci. Results: The heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk. Conclusions: We provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions.
KW - Parkinson's disease
KW - endocytosis
KW - genetic risk
KW - heritability
KW - polygenic risk score
UR - http://www.scopus.com/inward/record.url?scp=85060660189&partnerID=8YFLogxK
U2 - 10.1002/mds.27614
DO - 10.1002/mds.27614
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 30675927
AN - SCOPUS:85060660189
SN - 0885-3185
VL - 34
SP - 460
EP - 468
JO - Movement Disorders
JF - Movement Disorders
IS - 4
ER -