LRRK2 variation and dementia with Lewy bodies

Michael G. Heckman, Alexandra I. Soto-Ortolaza, Monica Y. Sanchez Contreras, Melissa E Murray, Otto D Pedraza, Nancy N. Diehl, Ronald Walton, Catherine Labbé, Oswaldo Lorenzo-Betancor, Ryan J. Uitti, Jay A Van Gerpen, Nilufer Taner, Glenn E. Smith, Kejal M Kantarci, Rodolfo Savica, David T Jones, Jonathan Graff-Radford, David S Knopman, Val Lowe, Clifford R Jr. JackRonald Carl Petersen, Joseph E Parisi, Rosa V Rademakers, Zbigniew K Wszolek, Neill R Graff Radford, Tanis Jill Ferman, Dennis W Dickson, Bradley F Boeve, Owen A Ross

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14 Citations (Scopus)

Abstract

Introduction The leucine-rich repeat kinase 2 (LRRK2) gene contains several variants that cause Parkinson's disease (PD) and others that modify PD risk. However, little is known about the role of LRRK2 in dementia with Lewy bodies (DLB). Aims of this study were to screen DLB patients for pathogenic LRRK2 variants and to evaluate associations between common LRRK2 variants and risk of DLB. Methods 417 clinical DLB patients and 1790 controls were included in the primary analysis. Additionally, 355 Lewy body disease patients assessed as having a high likelihood of clinical DLB based on neuropathological findings were included in secondary analysis. Seven pathogenic LRRK2 variants were assessed in patients, while 17 common LRRK2 exonic variants and 1 GWAS-nominated common LRRK2 PD-risk variant were evaluated for association with DLB. Results We identified carriers of 2 different pathogenic LRRK2 variants. One clinical DLB patient was a p.G2019S carrier, while in the pathological high likelihood DLB series there was one carrier of the p.R1441C mutation. However, examination of clinical records revealed the p.R1441C carrier to have PD with dementia. Evaluation of common variants did not reveal any associations with DLB risk after multiple testing adjustment. However, a non-significant trend similar to that previously reported for PD was observed for the protective p.N551K-R1398H-K1423K haplotype in the clinical DLB series (OR: 0.76, P = 0.061). Conclusion LRRK2 does not appear to play a major role in DLB, however further study of p.G2019S and the p.N551K-R1398H-K1423K haplotype is warranted to better understand their involvement in determining DLB risk.

Original languageEnglish (US)
Pages (from-to)98-103
Number of pages6
JournalParkinsonism and Related Disorders
Volume31
DOIs
StatePublished - Oct 1 2016

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Lewy Body Disease
Leucine
Phosphotransferases
Parkinson Disease
Haplotypes
Social Adjustment
Genome-Wide Association Study
Dementia

Keywords

  • Dementia with Lewy bodies
  • Genetics
  • LRRK2
  • Parkinson's disease

ASJC Scopus subject areas

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology

Cite this

LRRK2 variation and dementia with Lewy bodies. / Heckman, Michael G.; Soto-Ortolaza, Alexandra I.; Sanchez Contreras, Monica Y.; Murray, Melissa E; Pedraza, Otto D; Diehl, Nancy N.; Walton, Ronald; Labbé, Catherine; Lorenzo-Betancor, Oswaldo; Uitti, Ryan J.; Van Gerpen, Jay A; Taner, Nilufer; Smith, Glenn E.; Kantarci, Kejal M; Savica, Rodolfo; Jones, David T; Graff-Radford, Jonathan; Knopman, David S; Lowe, Val; Jack, Clifford R Jr.; Petersen, Ronald Carl; Parisi, Joseph E; Rademakers, Rosa V; Wszolek, Zbigniew K; Graff Radford, Neill R; Ferman, Tanis Jill; Dickson, Dennis W; Boeve, Bradley F; Ross, Owen A.

In: Parkinsonism and Related Disorders, Vol. 31, 01.10.2016, p. 98-103.

Research output: Contribution to journalArticle

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abstract = "Introduction The leucine-rich repeat kinase 2 (LRRK2) gene contains several variants that cause Parkinson's disease (PD) and others that modify PD risk. However, little is known about the role of LRRK2 in dementia with Lewy bodies (DLB). Aims of this study were to screen DLB patients for pathogenic LRRK2 variants and to evaluate associations between common LRRK2 variants and risk of DLB. Methods 417 clinical DLB patients and 1790 controls were included in the primary analysis. Additionally, 355 Lewy body disease patients assessed as having a high likelihood of clinical DLB based on neuropathological findings were included in secondary analysis. Seven pathogenic LRRK2 variants were assessed in patients, while 17 common LRRK2 exonic variants and 1 GWAS-nominated common LRRK2 PD-risk variant were evaluated for association with DLB. Results We identified carriers of 2 different pathogenic LRRK2 variants. One clinical DLB patient was a p.G2019S carrier, while in the pathological high likelihood DLB series there was one carrier of the p.R1441C mutation. However, examination of clinical records revealed the p.R1441C carrier to have PD with dementia. Evaluation of common variants did not reveal any associations with DLB risk after multiple testing adjustment. However, a non-significant trend similar to that previously reported for PD was observed for the protective p.N551K-R1398H-K1423K haplotype in the clinical DLB series (OR: 0.76, P = 0.061). Conclusion LRRK2 does not appear to play a major role in DLB, however further study of p.G2019S and the p.N551K-R1398H-K1423K haplotype is warranted to better understand their involvement in determining DLB risk.",
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T1 - LRRK2 variation and dementia with Lewy bodies

AU - Heckman, Michael G.

AU - Soto-Ortolaza, Alexandra I.

AU - Sanchez Contreras, Monica Y.

AU - Murray, Melissa E

AU - Pedraza, Otto D

AU - Diehl, Nancy N.

AU - Walton, Ronald

AU - Labbé, Catherine

AU - Lorenzo-Betancor, Oswaldo

AU - Uitti, Ryan J.

AU - Van Gerpen, Jay A

AU - Taner, Nilufer

AU - Smith, Glenn E.

AU - Kantarci, Kejal M

AU - Savica, Rodolfo

AU - Jones, David T

AU - Graff-Radford, Jonathan

AU - Knopman, David S

AU - Lowe, Val

AU - Jack, Clifford R Jr.

AU - Petersen, Ronald Carl

AU - Parisi, Joseph E

AU - Rademakers, Rosa V

AU - Wszolek, Zbigniew K

AU - Graff Radford, Neill R

AU - Ferman, Tanis Jill

AU - Dickson, Dennis W

AU - Boeve, Bradley F

AU - Ross, Owen A

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Introduction The leucine-rich repeat kinase 2 (LRRK2) gene contains several variants that cause Parkinson's disease (PD) and others that modify PD risk. However, little is known about the role of LRRK2 in dementia with Lewy bodies (DLB). Aims of this study were to screen DLB patients for pathogenic LRRK2 variants and to evaluate associations between common LRRK2 variants and risk of DLB. Methods 417 clinical DLB patients and 1790 controls were included in the primary analysis. Additionally, 355 Lewy body disease patients assessed as having a high likelihood of clinical DLB based on neuropathological findings were included in secondary analysis. Seven pathogenic LRRK2 variants were assessed in patients, while 17 common LRRK2 exonic variants and 1 GWAS-nominated common LRRK2 PD-risk variant were evaluated for association with DLB. Results We identified carriers of 2 different pathogenic LRRK2 variants. One clinical DLB patient was a p.G2019S carrier, while in the pathological high likelihood DLB series there was one carrier of the p.R1441C mutation. However, examination of clinical records revealed the p.R1441C carrier to have PD with dementia. Evaluation of common variants did not reveal any associations with DLB risk after multiple testing adjustment. However, a non-significant trend similar to that previously reported for PD was observed for the protective p.N551K-R1398H-K1423K haplotype in the clinical DLB series (OR: 0.76, P = 0.061). Conclusion LRRK2 does not appear to play a major role in DLB, however further study of p.G2019S and the p.N551K-R1398H-K1423K haplotype is warranted to better understand their involvement in determining DLB risk.

AB - Introduction The leucine-rich repeat kinase 2 (LRRK2) gene contains several variants that cause Parkinson's disease (PD) and others that modify PD risk. However, little is known about the role of LRRK2 in dementia with Lewy bodies (DLB). Aims of this study were to screen DLB patients for pathogenic LRRK2 variants and to evaluate associations between common LRRK2 variants and risk of DLB. Methods 417 clinical DLB patients and 1790 controls were included in the primary analysis. Additionally, 355 Lewy body disease patients assessed as having a high likelihood of clinical DLB based on neuropathological findings were included in secondary analysis. Seven pathogenic LRRK2 variants were assessed in patients, while 17 common LRRK2 exonic variants and 1 GWAS-nominated common LRRK2 PD-risk variant were evaluated for association with DLB. Results We identified carriers of 2 different pathogenic LRRK2 variants. One clinical DLB patient was a p.G2019S carrier, while in the pathological high likelihood DLB series there was one carrier of the p.R1441C mutation. However, examination of clinical records revealed the p.R1441C carrier to have PD with dementia. Evaluation of common variants did not reveal any associations with DLB risk after multiple testing adjustment. However, a non-significant trend similar to that previously reported for PD was observed for the protective p.N551K-R1398H-K1423K haplotype in the clinical DLB series (OR: 0.76, P = 0.061). Conclusion LRRK2 does not appear to play a major role in DLB, however further study of p.G2019S and the p.N551K-R1398H-K1423K haplotype is warranted to better understand their involvement in determining DLB risk.

KW - Dementia with Lewy bodies

KW - Genetics

KW - LRRK2

KW - Parkinson's disease

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