GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

Arvid Rongve; Aree Witoelar; Agustín Ruiz; Lavinia Athanasiu; Carla Abdelnour; Jordi Clarimon; Stefanie Heilmann-Heimbach; Isabel Hernández; Sonia Moreno-Grau; Itziar de Rojas; Estrella Morenas-Rodríguez; Tormod Fladby; Sigrid B. Sando; Geir Bråthen; Frédéric Blanc; Olivier Bousiges; Afina W. Lemstra; Inger van Steenoven; Elisabet Londos; Ina S. Almdahl; Lene Pålhaugen; Jon A. Eriksen; Srdjan Djurovic; Eystein Stordal; Ingvild Saltvedt; Ingun D. Ulstein; Francesco Bettella; Rahul S. Desikan; Ane Victoria Idland; Mathias Toft; Lasse Pihlstrøm; Jon Snaedal; Lluís Tárraga; Mercè Boada; Alberto Lleó; Hreinn Stefánsson; Kári Stefánsson; Alfredo Ramírez; Dag Aarsland; Ole A. Andreassen

doi:10.1038/s41598-019-43458-2

GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

Arvid Rongve, Aree Witoelar, Agustín Ruiz, Lavinia Athanasiu, Carla Abdelnour, Jordi Clarimon, Stefanie Heilmann-Heimbach, Isabel Hernández, Sonia Moreno-Grau, Itziar de Rojas, Estrella Morenas-Rodríguez, Tormod Fladby, Sigrid B. Sando, Geir Bråthen, Frédéric Blanc, Olivier Bousiges, Afina W. Lemstra, Inger van Steenoven, Elisabet Londos, Ina S. AlmdahlLene Pålhaugen, Jon A. Eriksen, Srdjan Djurovic, Eystein Stordal, Ingvild Saltvedt, Ingun D. Ulstein, Francesco Bettella, Rahul S. Desikan, Ane Victoria Idland, Mathias Toft, Lasse Pihlstrøm, Jon Snaedal, Lluís Tárraga, Mercè Boada, Alberto Lleó, Hreinn Stefánsson, Kári Stefánsson, Alfredo Ramírez, Dag Aarsland, Ole A. Andreassen

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Abstract

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10⁻⁸). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10⁻⁶. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

Original language	English (US)
Article number	7013
Journal	Scientific reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-43458-2
State	Published - Dec 1 2019
Externally published	Yes

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Rongve, A., Witoelar, A., Ruiz, A., Athanasiu, L., Abdelnour, C., Clarimon, J., Heilmann-Heimbach, S., Hernández, I., Moreno-Grau, S., de Rojas, I., Morenas-Rodríguez, E., Fladby, T., Sando, S. B., Bråthen, G., Blanc, F., Bousiges, O., Lemstra, A. W., van Steenoven, I., Londos, E., ... Andreassen, O. A. (2019). GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study. Scientific reports, 9(1), Article 7013. https://doi.org/10.1038/s41598-019-43458-2

Rongve, A, Witoelar, A, Ruiz, A, Athanasiu, L, Abdelnour, C, Clarimon, J, Heilmann-Heimbach, S, Hernández, I, Moreno-Grau, S, de Rojas, I, Morenas-Rodríguez, E, Fladby, T, Sando, SB, Bråthen, G, Blanc, F, Bousiges, O, Lemstra, AW, van Steenoven, I, Londos, E, Almdahl, IS, Pålhaugen, L, Eriksen, JA, Djurovic, S, Stordal, E, Saltvedt, I, Ulstein, ID, Bettella, F, Desikan, RS, Idland, AV, Toft, M, Pihlstrøm, L, Snaedal, J, Tárraga, L, Boada, M, Lleó, A, Stefánsson, H, Stefánsson, K, Ramírez, A, Aarsland, D & Andreassen, OA 2019, 'GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study', Scientific reports, vol. 9, no. 1, 7013. https://doi.org/10.1038/s41598-019-43458-2

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title = "GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study",

abstract = "Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer{\textquoteright}s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.",

author = "Arvid Rongve and Aree Witoelar and Agust{\'i}n Ruiz and Lavinia Athanasiu and Carla Abdelnour and Jordi Clarimon and Stefanie Heilmann-Heimbach and Isabel Hern{\'a}ndez and Sonia Moreno-Grau and {de Rojas}, Itziar and Estrella Morenas-Rodr{\'i}guez and Tormod Fladby and Sando, {Sigrid B.} and Geir Br{\aa}then and Fr{\'e}d{\'e}ric Blanc and Olivier Bousiges and Lemstra, {Afina W.} and {van Steenoven}, Inger and Elisabet Londos and Almdahl, {Ina S.} and Lene P{\aa}lhaugen and Eriksen, {Jon A.} and Srdjan Djurovic and Eystein Stordal and Ingvild Saltvedt and Ulstein, {Ingun D.} and Francesco Bettella and Desikan, {Rahul S.} and Idland, {Ane Victoria} and Mathias Toft and Lasse Pihlstr{\o}m and Jon Snaedal and Llu{\'i}s T{\'a}rraga and Merc{\`e} Boada and Alberto Lle{\'o} and Hreinn Stef{\'a}nsson and K{\'a}ri Stef{\'a}nsson and Alfredo Ram{\'i}rez and Dag Aarsland and Andreassen, {Ole A.}",

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year = "2019",

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doi = "10.1038/s41598-019-43458-2",

language = "English (US)",

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TY - JOUR

T1 - GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

AU - Rongve, Arvid

AU - Witoelar, Aree

AU - Ruiz, Agustín

AU - Athanasiu, Lavinia

AU - Abdelnour, Carla

AU - Clarimon, Jordi

AU - Heilmann-Heimbach, Stefanie

AU - Hernández, Isabel

AU - Moreno-Grau, Sonia

AU - de Rojas, Itziar

AU - Morenas-Rodríguez, Estrella

AU - Fladby, Tormod

AU - Sando, Sigrid B.

AU - Bråthen, Geir

AU - Blanc, Frédéric

AU - Bousiges, Olivier

AU - Lemstra, Afina W.

AU - van Steenoven, Inger

AU - Londos, Elisabet

AU - Almdahl, Ina S.

AU - Pålhaugen, Lene

AU - Eriksen, Jon A.

AU - Djurovic, Srdjan

AU - Stordal, Eystein

AU - Saltvedt, Ingvild

AU - Ulstein, Ingun D.

AU - Bettella, Francesco

AU - Desikan, Rahul S.

AU - Idland, Ane Victoria

AU - Toft, Mathias

AU - Pihlstrøm, Lasse

AU - Snaedal, Jon

AU - Tárraga, Lluís

AU - Boada, Mercè

AU - Lleó, Alberto

AU - Stefánsson, Hreinn

AU - Stefánsson, Kári

AU - Ramírez, Alfredo

AU - Aarsland, Dag

AU - Andreassen, Ole A.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

AB - Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

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U2 - 10.1038/s41598-019-43458-2

DO - 10.1038/s41598-019-43458-2

M3 - Article

C2 - 31065058

AN - SCOPUS:85065429787

SN - 2045-2322

VL - 9

JO - Scientific reports

JF - Scientific reports

IS - 1

M1 - 7013

ER -

GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

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