Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: Evidence for oligogenic inheritance

Steven J. Lubbe, Valentina Escott-Price, J. Raphael Gibbs, Mike A. Nalls, Jose Bras, T. Ryan Price, Aude Nicolas, Iris E. Jansen, Kin Y. Mok, Alan M. Pittman, James E. Tomkins, Patrick A. Lewis, Alastair J. Noyce, Suzanne Lesage, Manu Sharma, Elena R. Schiff, Adam P. Levine, Alexis Brice, Thomas Gasser, John Hardy & 5 others Peter Heutink, Nicholas W. Wood, Andrew B. Singleton, Nigel M. Williams, Huw R. Morris

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥ 30%) of cases with a recognised primary genetic cause had ≥ 1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.

Original languageEnglish
Pages (from-to)5483-5489
Number of pages7
JournalHuman Molecular Genetics
Volume25
Issue number24
DOIs
Publication statusPublished - 15 Dec 2016

Cite this

Lubbe, Steven J. ; Escott-Price, Valentina ; Gibbs, J. Raphael ; Nalls, Mike A. ; Bras, Jose ; Price, T. Ryan ; Nicolas, Aude ; Jansen, Iris E. ; Mok, Kin Y. ; Pittman, Alan M. ; Tomkins, James E. ; Lewis, Patrick A. ; Noyce, Alastair J. ; Lesage, Suzanne ; Sharma, Manu ; Schiff, Elena R. ; Levine, Adam P. ; Brice, Alexis ; Gasser, Thomas ; Hardy, John ; Heutink, Peter ; Wood, Nicholas W. ; Singleton, Andrew B. ; Williams, Nigel M. ; Morris, Huw R. / Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations : Evidence for oligogenic inheritance. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 24. pp. 5483-5489.
@article{7017aabe19c446ddb058f4bf5b7362c0,
title = "Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: Evidence for oligogenic inheritance",
abstract = "Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥ 30{\%}) of cases with a recognised primary genetic cause had ≥ 1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17{\%}) and unaffected controls (16{\%}), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10{\%} of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8{\%}) and controls (5{\%}), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.",
author = "Lubbe, {Steven J.} and Valentina Escott-Price and Gibbs, {J. Raphael} and Nalls, {Mike A.} and Jose Bras and Price, {T. Ryan} and Aude Nicolas and Jansen, {Iris E.} and Mok, {Kin Y.} and Pittman, {Alan M.} and Tomkins, {James E.} and Lewis, {Patrick A.} and Noyce, {Alastair J.} and Suzanne Lesage and Manu Sharma and Schiff, {Elena R.} and Levine, {Adam P.} and Alexis Brice and Thomas Gasser and John Hardy and Peter Heutink and Wood, {Nicholas W.} and Singleton, {Andrew B.} and Williams, {Nigel M.} and Morris, {Huw R.}",
year = "2016",
month = "12",
day = "15",
doi = "10.1093/hmg/ddw348",
language = "English",
volume = "25",
pages = "5483--5489",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "24",

}

Lubbe, SJ, Escott-Price, V, Gibbs, JR, Nalls, MA, Bras, J, Price, TR, Nicolas, A, Jansen, IE, Mok, KY, Pittman, AM, Tomkins, JE, Lewis, PA, Noyce, AJ, Lesage, S, Sharma, M, Schiff, ER, Levine, AP, Brice, A, Gasser, T, Hardy, J, Heutink, P, Wood, NW, Singleton, AB, Williams, NM & Morris, HR 2016, 'Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: Evidence for oligogenic inheritance' Human Molecular Genetics, vol. 25, no. 24, pp. 5483-5489. https://doi.org/10.1093/hmg/ddw348

Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations : Evidence for oligogenic inheritance. / Lubbe, Steven J.; Escott-Price, Valentina; Gibbs, J. Raphael; Nalls, Mike A.; Bras, Jose; Price, T. Ryan; Nicolas, Aude; Jansen, Iris E.; Mok, Kin Y.; Pittman, Alan M.; Tomkins, James E.; Lewis, Patrick A.; Noyce, Alastair J.; Lesage, Suzanne; Sharma, Manu; Schiff, Elena R.; Levine, Adam P.; Brice, Alexis; Gasser, Thomas; Hardy, John; Heutink, Peter; Wood, Nicholas W.; Singleton, Andrew B.; Williams, Nigel M.; Morris, Huw R.

In: Human Molecular Genetics, Vol. 25, No. 24, 15.12.2016, p. 5483-5489.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations

T2 - Evidence for oligogenic inheritance

AU - Lubbe, Steven J.

AU - Escott-Price, Valentina

AU - Gibbs, J. Raphael

AU - Nalls, Mike A.

AU - Bras, Jose

AU - Price, T. Ryan

AU - Nicolas, Aude

AU - Jansen, Iris E.

AU - Mok, Kin Y.

AU - Pittman, Alan M.

AU - Tomkins, James E.

AU - Lewis, Patrick A.

AU - Noyce, Alastair J.

AU - Lesage, Suzanne

AU - Sharma, Manu

AU - Schiff, Elena R.

AU - Levine, Adam P.

AU - Brice, Alexis

AU - Gasser, Thomas

AU - Hardy, John

AU - Heutink, Peter

AU - Wood, Nicholas W.

AU - Singleton, Andrew B.

AU - Williams, Nigel M.

AU - Morris, Huw R.

PY - 2016/12/15

Y1 - 2016/12/15

N2 - Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥ 30%) of cases with a recognised primary genetic cause had ≥ 1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.

AB - Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥ 30%) of cases with a recognised primary genetic cause had ≥ 1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.

UR - http://www.scopus.com/inward/record.url?scp=85016046155&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddw348

DO - 10.1093/hmg/ddw348

M3 - Article

VL - 25

SP - 5483

EP - 5489

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 24

ER -