Moving beyond neurons :: the role of cell type-specific gene regulation in Parkinson's disease heritability

Jaime Kulisevsky; R. H. Reynolds; J. Botía; M. A. Nalls; A. J. Noyce; A. Nicolas; M. R. Cookson; S. Bandres-Ciga; J. R. Gibbs; D. G. Hernandez; A. B. Singleton; X. Reed; H. Leonard; Cornelis Blauwendraat; F. Faghri; J. Bras; Rita Guerreiro; A. Tucci; Demis A Kia; Henry Houlden; H. Plun-Favreau; K. Y. Mok; N. W. Wood; R. Lovering; L. R'Bibo; M. Rizig; Viorica Chelban; D. Trabzuni; M. Tan; H. R. Morris; B. Middlehurst; J. Quinn; K. Billingsley; Peter Holmans; K. J. Kinghorn; P. Lewis; Valentina Escott-Price; N. Williams; T. Foltynie; Alexis Brice; F. Danjou; S. Lesage; Jean-Christophe Corvol; M. Martinez; A. Giri; C. Schulte; K. Brockmann; J. Simón-Sánchez; Peter Heutink; Thomas Gasser; P. Rizzu; M. Sharma; J. M. Shulman; L. Robak; S. Lubbe; N. E. Mencacci; S. Finkbeiner; C. Lungu; S. W. Scholz; Z. Gan-Or; G. A. Rouleau; L. Krohan; J. J. van Hilten; J. Marinus; A.D Adarmes-Gómez; I. Bernal-Bernal; Marta Bonilla-Toribio; Dolores Buiza-Rueda; F. Carrillo; M. Carrión-Claro; P. Mir; P. Gómez-Garre; S. Jesús; Miguel A Labrador-Espinosa; Daniel Macías-García; L. Vargas-González; C. Méndez-del-Barrio; T. Periñán-Tocino; C. Tejera-Parrado; Monica. Diez-Fairen; Miquel Aguilar Barberà; Ignacio Alvarez; M. T. Boungiorno; M. Carcel; Pau Pastor; J. P. Tartari; V. Alvarez; M. M. González; Marta Blázquez Estrada; C.. Garcia; E. Suarez-Sanmartin; F. J. Barrero; E. M. Rezola; J. A. B. Yarza; A. G. Pagola; A. L. de Munain Arregui; J. Ruiz-Martínez; Debora Cerdan; J. Duarte; Jordi Clarimón; Oriol Dols Icardo; J. Infante; J. Marín; Javier Pagonabarraga Mora; Isabel Gonzalez-Aramburu; A. S. Rodriguez; M. Sierra; Raquel Duran; C. Ruz; F. Vives; F. Escamilla-Sevilla; A. Mínguez; Ana Cámara; Yaroslau Compta; M. Ezquerra; M. J. Marti; M. Fernández; José Esteban Muñoz García; Rubén Fernández Santiago; E. Tolosa; F. Valldeoriola; P. García-Ruiz; M. J. G. Heredia; F. P. Errazquin; J. Hoenicka; A. Jimenez-Escrig; J. C. Martínez-Castrillo; J. L. Lopez-Sendon; I. M. Torres; C. Tabernero; Lydia Vela; Alexander Zimprich; L. Pihlstrom; S. Koks; P. Taba; K. Majamaa; A. Siitonen; N. U. Okubadejo; O. O. Ojo; T. Pitcher; T. Anderson; S. Bentley; J. Fowdar; G. Mellick; J. Dalrymple-Alford; Anjali K Henders; I. Kassam; G. Montgomery; J. Sidorenko; F. Zhang; A. Xue; C. L. Vallerga; Leanne Wallace; N. R. Wray; J. Yang; P. M. Visscher; J. Gratten; P. A. Silburn; G. Halliday; Ian B Hickie; J. Kwok; S. Lewis; M. Kennedy; J. Pearson; J. Hardy; S. A. Gagliano Taliun; Mina Ryten

doi:10.1038/s41531-019-0076-6

Moving beyond neurons : the role of cell type-specific gene regulation in Parkinson's disease heritability

Jaime Kulisevsky, R. H. Reynolds, J. Botía, M. A. Nalls, A. J. Noyce, A. Nicolas, M. R. Cookson, S. Bandres-Ciga, J. R. Gibbs, D. G. Hernandez, A. B. Singleton, X. Reed, H. Leonard, Cornelis Blauwendraat, F. Faghri, J. Bras, Rita Guerreiro, A. Tucci, Demis A Kia, Henry HouldenH. Plun-Favreau, K. Y. Mok, N. W. Wood, R. Lovering, L. R'Bibo, M. Rizig, Viorica Chelban, D. Trabzuni, M. Tan, H. R. Morris, B. Middlehurst, J. Quinn, K. Billingsley, Peter Holmans, K. J. Kinghorn, P. Lewis, Valentina Escott-Price, N. Williams, T. Foltynie, Alexis Brice, F. Danjou, S. Lesage, Jean-Christophe Corvol, M. Martinez, A. Giri, C. Schulte, K. Brockmann, J. Simón-Sánchez, Peter Heutink, Thomas Gasser, P. Rizzu, M. Sharma, J. M. Shulman, L. Robak, S. Lubbe, N. E. Mencacci, S. Finkbeiner, C. Lungu, S. W. Scholz, Z. Gan-Or, G. A. Rouleau, L. Krohan, J. J. van Hilten, J. Marinus, A.D Adarmes-Gómez, I. Bernal-Bernal, Marta Bonilla-Toribio, Dolores Buiza-Rueda, F. Carrillo, M. Carrión-Claro, P. Mir, P. Gómez-Garre, S. Jesús, Miguel A Labrador-Espinosa, Daniel Macías-García, L. Vargas-González, C. Méndez-del-Barrio, T. Periñán-Tocino, C. Tejera-Parrado, Monica. Diez-Fairen, Miquel Aguilar Barberà, Ignacio Alvarez, M. T. Boungiorno, M. Carcel, Pau Pastor, J. P. Tartari, V. Alvarez, M. M. González, Marta Blázquez Estrada, C.. Garcia, E. Suarez-Sanmartin, F. J. Barrero, E. M. Rezola, J. A. B. Yarza, A. G. Pagola, A. L. de Munain Arregui, J. Ruiz-Martínez, Debora Cerdan, J. Duarte, Jordi Clarimón, Oriol Dols Icardo, J. Infante, J. Marín, Javier Pagonabarraga Mora, Isabel Gonzalez-Aramburu, A. S. Rodriguez, M. Sierra, Raquel Duran, C. Ruz, F. Vives, F. Escamilla-Sevilla, A. Mínguez, Ana Cámara, Yaroslau Compta, M. Ezquerra, M. J. Marti, M. Fernández, José Esteban Muñoz García, Rubén Fernández Santiago, E. Tolosa, F. Valldeoriola, P. García-Ruiz, M. J. G. Heredia, F. P. Errazquin, J. Hoenicka, A. Jimenez-Escrig, J. C. Martínez-Castrillo, J. L. Lopez-Sendon, I. M. Torres, C. Tabernero, Lydia Vela, Alexander Zimprich, L. Pihlstrom, S. Koks, P. Taba, K. Majamaa, A. Siitonen, N. U. Okubadejo, O. O. Ojo, T. Pitcher, T. Anderson, S. Bentley, J. Fowdar, G. Mellick, J. Dalrymple-Alford, Anjali K Henders, I. Kassam, G. Montgomery, J. Sidorenko, F. Zhang, A. Xue, C. L. Vallerga, Leanne Wallace, N. R. Wray, J. Yang, P. M. Visscher, J. Gratten, P. A. Silburn, G. Halliday, Ian B Hickie, J. Kwok, S. Lewis, M. Kennedy, J. Pearson, J. Hardy, S. A. Gagliano Taliun, Mina Ryten

Departament de Medicina

Producció científica: Contribució a revista › Article › Recerca › Avaluat per experts

64 Cites (Scopus)

Resum

Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

Idioma original	Anglès
Revista	npj Parkinson's Disease
Volum	5
Número	1
DOIs	https://doi.org/10.1038/s41531-019-0076-6
Estat de la publicació	Publicada - 2019

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Aquest resultat contribueix als següents objectius de desenvolupament sostenible.

Accés al document

10.1038/s41531-019-0076-6

https://ddd.uab.cat/record/223586

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Kulisevsky, J., Reynolds, R. H., Botía, J., Nalls, M. A., Noyce, A. J., Nicolas, A., Cookson, M. R., Bandres-Ciga, S., Gibbs, J. R., Hernandez, D. G., Singleton, A. B., Reed, X., Leonard, H., Blauwendraat, C., Faghri, F., Bras, J., Guerreiro, R., Tucci, A., Kia, D. A., ... Ryten, M. (2019). Moving beyond neurons : the role of cell type-specific gene regulation in Parkinson's disease heritability. npj Parkinson's Disease, 5(1). https://doi.org/10.1038/s41531-019-0076-6

@article{391c6b0e720c4c85a874a60b19fb6b59,

title = "Moving beyond neurons :: the role of cell type-specific gene regulation in Parkinson's disease heritability",

abstract = "Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.",

author = "Jaime Kulisevsky and Reynolds, {R. H.} and J. Bot{\'i}a and Nalls, {M. A.} and Noyce, {A. J.} and A. Nicolas and Cookson, {M. R.} and S. Bandres-Ciga and Gibbs, {J. R.} and Hernandez, {D. G.} and Singleton, {A. B.} and X. Reed and H. Leonard and Cornelis Blauwendraat and F. Faghri and J. Bras and Rita Guerreiro and A. Tucci and Kia, {Demis A} and Henry Houlden and H. Plun-Favreau and Mok, {K. Y.} and Wood, {N. W.} and R. Lovering and L. R'Bibo and M. Rizig and Viorica Chelban and D. Trabzuni and M. Tan and Morris, {H. R.} and B. Middlehurst and J. Quinn and K. Billingsley and Peter Holmans and Kinghorn, {K. J.} and P. Lewis and Valentina Escott-Price and N. Williams and T. Foltynie and Alexis Brice and F. Danjou and S. Lesage and Jean-Christophe Corvol and M. Martinez and A. Giri and C. Schulte and K. Brockmann and J. Sim{\'o}n-S{\'a}nchez and Peter Heutink and Thomas Gasser and P. Rizzu and M. Sharma and Shulman, {J. M.} and L. Robak and S. Lubbe and Mencacci, {N. E.} and S. Finkbeiner and C. Lungu and Scholz, {S. W.} and Z. Gan-Or and Rouleau, {G. A.} and L. Krohan and {van Hilten}, {J. J.} and J. Marinus and A.D Adarmes-G{\'o}mez and I. Bernal-Bernal and Marta Bonilla-Toribio and Dolores Buiza-Rueda and F. Carrillo and M. Carri{\'o}n-Claro and P. Mir and P. G{\'o}mez-Garre and S. Jes{\'u}s and Labrador-Espinosa, {Miguel A} and Daniel Mac{\'i}as-Garc{\'i}a and L. Vargas-Gonz{\'a}lez and C. M{\'e}ndez-del-Barrio and T. Peri{\~n}{\'a}n-Tocino and C. Tejera-Parrado and Monica. Diez-Fairen and {Aguilar Barber{\`a}}, Miquel and Ignacio Alvarez and Boungiorno, {M. T.} and M. Carcel and Pau Pastor and Tartari, {J. P.} and V. Alvarez and Gonz{\'a}lez, {M. M.} and {Bl{\'a}zquez Estrada}, Marta and C.. Garcia and E. Suarez-Sanmartin and Barrero, {F. J.} and Rezola, {E. M.} and Yarza, {J. A. B.} and Pagola, {A. G.} and {de Munain Arregui}, {A. L.} and J. Ruiz-Mart{\'i}nez and Debora Cerdan and J. Duarte and Jordi Clarim{\'o}n and {Dols Icardo}, Oriol and J. Infante and J. Mar{\'i}n and {Pagonabarraga Mora}, Javier and Isabel Gonzalez-Aramburu and Rodriguez, {A. S.} and M. Sierra and Raquel Duran and C. Ruz and F. Vives and F. Escamilla-Sevilla and A. M{\'i}nguez and Ana C{\'a}mara and Yaroslau Compta and M. Ezquerra and Marti, {M. J.} and M. Fern{\'a}ndez and {Mu{\~n}oz Garc{\'i}a}, {Jos{\'e} Esteban} and {Fern{\'a}ndez Santiago}, Rub{\'e}n and E. Tolosa and F. Valldeoriola and P. Garc{\'i}a-Ruiz and Heredia, {M. J. G.} and Errazquin, {F. P.} and J. Hoenicka and A. Jimenez-Escrig and Mart{\'i}nez-Castrillo, {J. C.} and Lopez-Sendon, {J. L.} and Torres, {I. M.} and C. Tabernero and Lydia Vela and Alexander Zimprich and L. Pihlstrom and S. Koks and P. Taba and K. Majamaa and A. Siitonen and Okubadejo, {N. U.} and Ojo, {O. O.} and T. Pitcher and T. Anderson and S. Bentley and J. Fowdar and G. Mellick and J. Dalrymple-Alford and Henders, {Anjali K} and I. Kassam and G. Montgomery and J. Sidorenko and F. Zhang and A. Xue and Vallerga, {C. L.} and Leanne Wallace and Wray, {N. R.} and J. Yang and Visscher, {P. M.} and J. Gratten and Silburn, {P. A.} and G. Halliday and Hickie, {Ian B} and J. Kwok and S. Lewis and M. Kennedy and J. Pearson and J. Hardy and {Gagliano Taliun}, {S. A.} and Mina Ryten",

year = "2019",

doi = "10.1038/s41531-019-0076-6",

language = "English",

volume = "5",

journal = "npj Parkinson's Disease",

issn = "2373-8057",

publisher = "Springer Nature",

number = "1",

}

Kulisevsky, J, Reynolds, RH, Botía, J, Nalls, MA, Noyce, AJ, Nicolas, A, Cookson, MR, Bandres-Ciga, S, Gibbs, JR, Hernandez, DG, Singleton, AB, Reed, X, Leonard, H, Blauwendraat, C, Faghri, F, Bras, J, Guerreiro, R, Tucci, A, Kia, DA, Houlden, H, Plun-Favreau, H, Mok, KY, Wood, NW, Lovering, R, R'Bibo, L, Rizig, M, Chelban, V, Trabzuni, D, Tan, M, Morris, HR, Middlehurst, B, Quinn, J, Billingsley, K, Holmans, P, Kinghorn, KJ, Lewis, P, Escott-Price, V, Williams, N, Foltynie, T, Brice, A, Danjou, F, Lesage, S, Corvol, J-C, Martinez, M, Giri, A, Schulte, C, Brockmann, K, Simón-Sánchez, J, Heutink, P, Gasser, T, Rizzu, P, Sharma, M, Shulman, JM, Robak, L, Lubbe, S, Mencacci, NE, Finkbeiner, S, Lungu, C, Scholz, SW, Gan-Or, Z, Rouleau, GA, Krohan, L, van Hilten, JJ, Marinus, J, Adarmes-Gómez, AD, Bernal-Bernal, I, Bonilla-Toribio, M, Buiza-Rueda, D, Carrillo, F, Carrión-Claro, M, Mir, P, Gómez-Garre, P, Jesús, S, Labrador-Espinosa, MA, Macías-García, D, Vargas-González, L, Méndez-del-Barrio, C, Periñán-Tocino, T, Tejera-Parrado, C, Diez-Fairen, M, Aguilar Barberà, M, Alvarez, I, Boungiorno, MT, Carcel, M, Pastor, P, Tartari, JP, Alvarez, V, González, MM, Blázquez Estrada, M, Garcia, C, Suarez-Sanmartin, E, Barrero, FJ, Rezola, EM, Yarza, JAB, Pagola, AG, de Munain Arregui, AL, Ruiz-Martínez, J, Cerdan, D, Duarte, J, Clarimón, J, Dols Icardo, O, Infante, J, Marín, J, Pagonabarraga Mora, J, Gonzalez-Aramburu, I, Rodriguez, AS, Sierra, M, Duran, R, Ruz, C, Vives, F, Escamilla-Sevilla, F, Mínguez, A, Cámara, A, Compta, Y, Ezquerra, M, Marti, MJ, Fernández, M, Muñoz García, JE, Fernández Santiago, R, Tolosa, E, Valldeoriola, F, García-Ruiz, P, Heredia, MJG, Errazquin, FP, Hoenicka, J, Jimenez-Escrig, A, Martínez-Castrillo, JC, Lopez-Sendon, JL, Torres, IM, Tabernero, C, Vela, L, Zimprich, A, Pihlstrom, L, Koks, S, Taba, P, Majamaa, K, Siitonen, A, Okubadejo, NU, Ojo, OO, Pitcher, T, Anderson, T, Bentley, S, Fowdar, J, Mellick, G, Dalrymple-Alford, J, Henders, AK, Kassam, I, Montgomery, G, Sidorenko, J, Zhang, F, Xue, A, Vallerga, CL, Wallace, L, Wray, NR, Yang, J, Visscher, PM, Gratten, J, Silburn, PA, Halliday, G, Hickie, IB, Kwok, J, Lewis, S, Kennedy, M, Pearson, J, Hardy, J, Gagliano Taliun, SA & Ryten, M 2019, 'Moving beyond neurons : the role of cell type-specific gene regulation in Parkinson's disease heritability', npj Parkinson's Disease, vol. 5, núm. 1. https://doi.org/10.1038/s41531-019-0076-6

TY - JOUR

T1 - Moving beyond neurons :

T2 - the role of cell type-specific gene regulation in Parkinson's disease heritability

AU - Kulisevsky, Jaime

AU - Reynolds, R. H.

AU - Botía, J.

AU - Nalls, M. A.

AU - Noyce, A. J.

AU - Nicolas, A.

AU - Cookson, M. R.

AU - Bandres-Ciga, S.

AU - Gibbs, J. R.

AU - Hernandez, D. G.

AU - Singleton, A. B.

AU - Reed, X.

AU - Leonard, H.

AU - Blauwendraat, Cornelis

AU - Faghri, F.

AU - Bras, J.

AU - Guerreiro, Rita

AU - Tucci, A.

AU - Kia, Demis A

AU - Houlden, Henry

AU - Plun-Favreau, H.

AU - Mok, K. Y.

AU - Wood, N. W.

AU - Lovering, R.

AU - R'Bibo, L.

AU - Rizig, M.

AU - Chelban, Viorica

AU - Trabzuni, D.

AU - Tan, M.

AU - Morris, H. R.

AU - Middlehurst, B.

AU - Quinn, J.

AU - Billingsley, K.

AU - Holmans, Peter

AU - Kinghorn, K. J.

AU - Lewis, P.

AU - Escott-Price, Valentina

AU - Williams, N.

AU - Foltynie, T.

AU - Brice, Alexis

AU - Danjou, F.

AU - Lesage, S.

AU - Corvol, Jean-Christophe

AU - Martinez, M.

AU - Giri, A.

AU - Schulte, C.

AU - Brockmann, K.

AU - Simón-Sánchez, J.

AU - Heutink, Peter

AU - Gasser, Thomas

AU - Rizzu, P.

AU - Sharma, M.

AU - Shulman, J. M.

AU - Robak, L.

AU - Lubbe, S.

AU - Mencacci, N. E.

AU - Finkbeiner, S.

AU - Lungu, C.

AU - Scholz, S. W.

AU - Gan-Or, Z.

AU - Rouleau, G. A.

AU - Krohan, L.

AU - van Hilten, J. J.

AU - Marinus, J.

AU - Adarmes-Gómez, A.D

AU - Bernal-Bernal, I.

AU - Bonilla-Toribio, Marta

AU - Buiza-Rueda, Dolores

AU - Carrillo, F.

AU - Carrión-Claro, M.

AU - Mir, P.

AU - Gómez-Garre, P.

AU - Jesús, S.

AU - Labrador-Espinosa, Miguel A

AU - Macías-García, Daniel

AU - Vargas-González, L.

AU - Méndez-del-Barrio, C.

AU - Periñán-Tocino, T.

AU - Tejera-Parrado, C.

AU - Diez-Fairen, Monica.

AU - Aguilar Barberà, Miquel

AU - Alvarez, Ignacio

AU - Boungiorno, M. T.

AU - Carcel, M.

AU - Pastor, Pau

AU - Tartari, J. P.

AU - Alvarez, V.

AU - González, M. M.

AU - Blázquez Estrada, Marta

AU - Garcia, C..

AU - Suarez-Sanmartin, E.

AU - Barrero, F. J.

AU - Rezola, E. M.

AU - Yarza, J. A. B.

AU - Pagola, A. G.

AU - de Munain Arregui, A. L.

AU - Ruiz-Martínez, J.

AU - Cerdan, Debora

AU - Duarte, J.

AU - Clarimón, Jordi

AU - Dols Icardo, Oriol

AU - Infante, J.

AU - Marín, J.

AU - Pagonabarraga Mora, Javier

AU - Gonzalez-Aramburu, Isabel

AU - Rodriguez, A. S.

AU - Sierra, M.

AU - Duran, Raquel

AU - Ruz, C.

AU - Vives, F.

AU - Escamilla-Sevilla, F.

AU - Mínguez, A.

AU - Cámara, Ana

AU - Compta, Yaroslau

AU - Ezquerra, M.

AU - Marti, M. J.

AU - Fernández, M.

AU - Muñoz García, José Esteban

AU - Fernández Santiago, Rubén

AU - Tolosa, E.

AU - Valldeoriola, F.

AU - García-Ruiz, P.

AU - Heredia, M. J. G.

AU - Errazquin, F. P.

AU - Hoenicka, J.

AU - Jimenez-Escrig, A.

AU - Martínez-Castrillo, J. C.

AU - Lopez-Sendon, J. L.

AU - Torres, I. M.

AU - Tabernero, C.

AU - Vela, Lydia

AU - Zimprich, Alexander

AU - Pihlstrom, L.

AU - Koks, S.

AU - Taba, P.

AU - Majamaa, K.

AU - Siitonen, A.

AU - Okubadejo, N. U.

AU - Ojo, O. O.

AU - Pitcher, T.

AU - Anderson, T.

AU - Bentley, S.

AU - Fowdar, J.

AU - Mellick, G.

AU - Dalrymple-Alford, J.

AU - Henders, Anjali K

AU - Kassam, I.

AU - Montgomery, G.

AU - Sidorenko, J.

AU - Zhang, F.

AU - Xue, A.

AU - Vallerga, C. L.

AU - Wallace, Leanne

AU - Wray, N. R.

AU - Yang, J.

AU - Visscher, P. M.

AU - Gratten, J.

AU - Silburn, P. A.

AU - Halliday, G.

AU - Hickie, Ian B

AU - Kwok, J.

AU - Lewis, S.

AU - Kennedy, M.

AU - Pearson, J.

AU - Hardy, J.

AU - Gagliano Taliun, S. A.

AU - Ryten, Mina

PY - 2019

Y1 - 2019

N2 - Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

AB - Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

U2 - 10.1038/s41531-019-0076-6

DO - 10.1038/s41531-019-0076-6

M3 - Article

C2 - 31016231

SN - 2373-8057

VL - 5

JO - npj Parkinson's Disease

JF - npj Parkinson's Disease

IS - 1

ER -

Moving beyond neurons : the role of cell type-specific gene regulation in Parkinson's disease heritability

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