Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease

Ignacio F. Mata; Catherine O. Johnson; James B. Leverenz; Daniel Weintraub; John Q. Trojanowski; Vivianna M. Van Deerlin; Beate Ritz; Rebecca Rausch; Stewart A. Factor; Cathy Wood-Siverio; Joseph F. Quinn; Kathryn A. Chung; Amie L. Peterson-Hiller; Alberto J. Espay; Fredy J. Revilla; Johnna Devoto; Dora Yearout; Shu Ching Hu; Brenna A. Cholerton; Thomas J. Montine; Karen L. Edwards; Cyrus P. Zabetian

doi:10.1016/j.neurobiolaging.2017.04.009

Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease

Ignacio F. Mata, Catherine O. Johnson, James B. Leverenz, Daniel Weintraub, John Q. Trojanowski, Vivianna M. Van Deerlin, Beate Ritz, Rebecca Rausch, Stewart A. Factor, Cathy Wood-Siverio, Joseph F. Quinn, Kathryn A. Chung, Amie L. Peterson-Hiller, Alberto J. Espay, Fredy J. Revilla, Johnna Devoto, Dora Yearout, Shu Ching Hu, Brenna A. Cholerton, Thomas J. MontineKaren L. Edwards, Cyrus P. Zabetian

Neurology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (P_FDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; P_FDR = 2.7 × 10⁻⁴) for JoLO, PARP4 rs9318600 (P_FDR = 0.006), and rs9581094 (P_FDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (P_FDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.

Original language	English (US)
Pages (from-to)	211.e1-211.e7
Journal	Neurobiology of Aging
Volume	56
DOIs	https://doi.org/10.1016/j.neurobiolaging.2017.04.009
State	Published - Aug 2017

Keywords

Cognitive impairment
Genetics
NeuroX
Parkinson's disease

ASJC Scopus subject areas

Clinical Neurology
Geriatrics and Gerontology
Aging
General Neuroscience
Developmental Biology

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10.1016/j.neurobiolaging.2017.04.009

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Mata, I. F., Johnson, C. O., Leverenz, J. B., Weintraub, D., Trojanowski, J. Q., Van Deerlin, V. M., Ritz, B., Rausch, R., Factor, S. A., Wood-Siverio, C., Quinn, J. F., Chung, K. A., Peterson-Hiller, A. L., Espay, A. J., Revilla, F. J., Devoto, J., Yearout, D., Hu, S. C., Cholerton, B. A., ... Zabetian, C. P. (2017). Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease. Neurobiology of Aging, 56, 211.e1-211.e7. https://doi.org/10.1016/j.neurobiolaging.2017.04.009

Mata, IF, Johnson, CO, Leverenz, JB, Weintraub, D, Trojanowski, JQ, Van Deerlin, VM, Ritz, B, Rausch, R, Factor, SA, Wood-Siverio, C, Quinn, JF , Chung, KA , Peterson-Hiller, AL, Espay, AJ, Revilla, FJ, Devoto, J, Yearout, D, Hu, SC, Cholerton, BA, Montine, TJ, Edwards, KL & Zabetian, CP 2017, 'Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease', Neurobiology of Aging, vol. 56, pp. 211.e1-211.e7. https://doi.org/10.1016/j.neurobiolaging.2017.04.009

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title = "Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease",

abstract = "Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (PFDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 × 10−4) for JoLO, PARP4 rs9318600 (PFDR = 0.006), and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.",

keywords = "Cognitive impairment, Genetics, NeuroX, Parkinson's disease",

author = "Mata, {Ignacio F.} and Johnson, {Catherine O.} and Leverenz, {James B.} and Daniel Weintraub and Trojanowski, {John Q.} and {Van Deerlin}, {Vivianna M.} and Beate Ritz and Rebecca Rausch and Factor, {Stewart A.} and Cathy Wood-Siverio and Quinn, {Joseph F.} and Chung, {Kathryn A.} and Peterson-Hiller, {Amie L.} and Espay, {Alberto J.} and Revilla, {Fredy J.} and Johnna Devoto and Dora Yearout and Hu, {Shu Ching} and Cholerton, {Brenna A.} and Montine, {Thomas J.} and Edwards, {Karen L.} and Zabetian, {Cyrus P.}",

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year = "2017",

month = aug,

doi = "10.1016/j.neurobiolaging.2017.04.009",

language = "English (US)",

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AU - Mata, Ignacio F.

AU - Johnson, Catherine O.

AU - Leverenz, James B.

AU - Weintraub, Daniel

AU - Trojanowski, John Q.

AU - Van Deerlin, Vivianna M.

AU - Ritz, Beate

AU - Rausch, Rebecca

AU - Factor, Stewart A.

AU - Wood-Siverio, Cathy

AU - Quinn, Joseph F.

AU - Chung, Kathryn A.

AU - Peterson-Hiller, Amie L.

AU - Espay, Alberto J.

AU - Revilla, Fredy J.

AU - Devoto, Johnna

AU - Yearout, Dora

AU - Hu, Shu Ching

AU - Cholerton, Brenna A.

AU - Montine, Thomas J.

AU - Edwards, Karen L.

AU - Zabetian, Cyrus P.

PY - 2017/8

Y1 - 2017/8

N2 - Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (PFDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 × 10−4) for JoLO, PARP4 rs9318600 (PFDR = 0.006), and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.

AB - Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (PFDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 × 10−4) for JoLO, PARP4 rs9318600 (PFDR = 0.006), and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.

KW - Cognitive impairment

KW - Genetics

KW - NeuroX

KW - Parkinson's disease

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JF - Neurobiology of Aging

ER -

Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease

Abstract

Keywords

ASJC Scopus subject areas

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