Genomewide association study for susceptibility genes contributing to familial Parkinson disease

Nathan Pankratz, Jemma B. Wilk, Jeanne C. Latourelle, Anita L. DeStefano, Cheryl Halter, Elizabeth W. Pugh, Kimberly F. Doheny, James F. Gusella, William C. Nichols, Tatiana Foroud, Richard H. Myers

Research output: Contribution to journalArticle

297 Citations (Scopus)

Abstract

Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 × 10-6; OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 × 10-5; OR = 1.35) and MAPT (recessive model: p = 2.0 × 10-5; OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case-control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 × 10-7) and the MAPT region (recessive model: p = 9.8 × 10-6; additive model: p = 4.8 × 10-5). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility.

Original languageEnglish
Pages (from-to)593-605
Number of pages13
JournalHuman Genetics
Volume124
Issue number6
DOIs
StatePublished - 2009

Fingerprint

Parkinson Disease
Genes
Disease Susceptibility
Chromosomes, Human, Pair 4
Single Nucleotide Polymorphism
Meta-Analysis
Logistic Models
Alleles
Mutation

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Pankratz, N., Wilk, J. B., Latourelle, J. C., DeStefano, A. L., Halter, C., Pugh, E. W., ... Myers, R. H. (2009). Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Human Genetics, 124(6), 593-605. https://doi.org/10.1007/s00439-008-0582-9

Genomewide association study for susceptibility genes contributing to familial Parkinson disease. / Pankratz, Nathan; Wilk, Jemma B.; Latourelle, Jeanne C.; DeStefano, Anita L.; Halter, Cheryl; Pugh, Elizabeth W.; Doheny, Kimberly F.; Gusella, James F.; Nichols, William C.; Foroud, Tatiana; Myers, Richard H.

In: Human Genetics, Vol. 124, No. 6, 2009, p. 593-605.

Research output: Contribution to journalArticle

Pankratz, N, Wilk, JB, Latourelle, JC, DeStefano, AL, Halter, C, Pugh, EW, Doheny, KF, Gusella, JF, Nichols, WC, Foroud, T & Myers, RH 2009, 'Genomewide association study for susceptibility genes contributing to familial Parkinson disease', Human Genetics, vol. 124, no. 6, pp. 593-605. https://doi.org/10.1007/s00439-008-0582-9
Pankratz, Nathan ; Wilk, Jemma B. ; Latourelle, Jeanne C. ; DeStefano, Anita L. ; Halter, Cheryl ; Pugh, Elizabeth W. ; Doheny, Kimberly F. ; Gusella, James F. ; Nichols, William C. ; Foroud, Tatiana ; Myers, Richard H. / Genomewide association study for susceptibility genes contributing to familial Parkinson disease. In: Human Genetics. 2009 ; Vol. 124, No. 6. pp. 593-605.
@article{4b794e341a5f41de8f04d84bc631cc77,
title = "Genomewide association study for susceptibility genes contributing to familial Parkinson disease",
abstract = "Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5{\%} of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 × 10-6; OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 × 10-5; OR = 1.35) and MAPT (recessive model: p = 2.0 × 10-5; OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case-control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 × 10-7) and the MAPT region (recessive model: p = 9.8 × 10-6; additive model: p = 4.8 × 10-5). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility.",
author = "Nathan Pankratz and Wilk, {Jemma B.} and Latourelle, {Jeanne C.} and DeStefano, {Anita L.} and Cheryl Halter and Pugh, {Elizabeth W.} and Doheny, {Kimberly F.} and Gusella, {James F.} and Nichols, {William C.} and Tatiana Foroud and Myers, {Richard H.}",
year = "2009",
doi = "10.1007/s00439-008-0582-9",
language = "English",
volume = "124",
pages = "593--605",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "6",

}

TY - JOUR

T1 - Genomewide association study for susceptibility genes contributing to familial Parkinson disease

AU - Pankratz, Nathan

AU - Wilk, Jemma B.

AU - Latourelle, Jeanne C.

AU - DeStefano, Anita L.

AU - Halter, Cheryl

AU - Pugh, Elizabeth W.

AU - Doheny, Kimberly F.

AU - Gusella, James F.

AU - Nichols, William C.

AU - Foroud, Tatiana

AU - Myers, Richard H.

PY - 2009

Y1 - 2009

N2 - Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 × 10-6; OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 × 10-5; OR = 1.35) and MAPT (recessive model: p = 2.0 × 10-5; OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case-control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 × 10-7) and the MAPT region (recessive model: p = 9.8 × 10-6; additive model: p = 4.8 × 10-5). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility.

AB - Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 × 10-6; OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 × 10-5; OR = 1.35) and MAPT (recessive model: p = 2.0 × 10-5; OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case-control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 × 10-7) and the MAPT region (recessive model: p = 9.8 × 10-6; additive model: p = 4.8 × 10-5). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility.

UR - http://www.scopus.com/inward/record.url?scp=58149100151&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149100151&partnerID=8YFLogxK

U2 - 10.1007/s00439-008-0582-9

DO - 10.1007/s00439-008-0582-9

M3 - Article

C2 - 18985386

AN - SCOPUS:58149100151

VL - 124

SP - 593

EP - 605

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 6

ER -