GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis

Astros Th. Skuladottir; Lilja Stefansdottir; Gisli H. Halldorsson; Olafur A. Stefansson; Anna Bjornsdottir; Palmi Jonsson; Vala Palmadottir; Thorgeir E. Thorgeirsson; G. Bragi Walters; Rosa S. Gisladottir; Gyda Bjornsdottir; Gudrun A. Jonsdottir; Patrick Sulem; Daniel F. Gudbjartsson; Kirk U. Knowlton; David A. Jones; Aigar Ottas; Tõnu Esko; Reedik Mägi; Mari Nelis; Georgi Hudjashov; Ole B. Pedersen; Maria Didriksen; Søren Brunak; Karina Banasik; Thomas Folkmann Hansen; Christian Erikstrup; DBDS Genomic Consortium; Jakob Bay; Jens Kjærgaard Boldsen; Thorsten Brodersen; Kristoffer Burgdorf; Mona Ameri Chalmer; Khoa Manh Dinh; Joseph Dowsett; Bjarke Feenstra; Frank Geller; Daniel Gudbjartsson; Lotte Hindhede; Henrik Hjalgrim; Rikke Louise Jacobsen; Gregor Jemec; Bitten Aagaard Jensen; Katrine Kaspersen; Bertram Dalskov Kjerulff; Lisette Kogelman; Margit Anita Hørup Larsen; Ioannis Louloudis; Agnete Lundgaard; Susan Mikkelsen; Christina Mikkelsen; Ioanna Nissen; Mette Nyegaard; Ole Birger Pedersen; Alexander Pil Henriksen; Palle Duun Rohde; Klaus Rostgaard; Michael Schwinn; Hreinn Stefansson; Erik Sørensen; Unnur Þorsteinsdóttir; Lise Wegner Thørner; Mie Topholm Bruun; Henrik Ullum; Thomas Werge; David Westergaard; Jan Haavik; Ole A. Andreassen; David Rye; Jannicke Igland; Sisse Rye Ostrowski; Lili A. Milani; Lincoln D. Nadauld; Hreinn Stefansson; Kari Stefansson

doi:10.1038/s42003-024-06207-4

GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis

Astros Th. Skuladottir, Lilja Stefansdottir, Gisli H. Halldorsson, Olafur A. Stefansson, Anna Bjornsdottir, Palmi Jonsson, Vala Palmadottir, Thorgeir E. Thorgeirsson, G. Bragi Walters, Rosa S. Gisladottir, Gyda Bjornsdottir, Gudrun A. Jonsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Kirk U. Knowlton, David A. Jones, Aigar Ottas, Tõnu Esko, Reedik Mägi, Mari NelisGeorgi Hudjashov, Ole B. Pedersen, Maria Didriksen, Søren Brunak, Karina Banasik, Thomas Folkmann Hansen, Christian Erikstrup, DBDS Genomic Consortium, Jakob Bay (Member of study group), Jens Kjærgaard Boldsen (Member of study group), Thorsten Brodersen (Member of study group), Kristoffer Burgdorf (Member of study group), Mona Ameri Chalmer (Member of study group), Khoa Manh Dinh (Member of study group), Joseph Dowsett (Member of study group), Bjarke Feenstra (Member of study group), Frank Geller (Member of study group), Daniel Gudbjartsson (Member of study group), Lotte Hindhede (Member of study group), Henrik Hjalgrim (Member of study group), Rikke Louise Jacobsen (Member of study group), Gregor Jemec (Member of study group), Bitten Aagaard Jensen (Member of study group), Katrine Kaspersen (Member of study group), Bertram Dalskov Kjerulff (Member of study group), Lisette Kogelman, Margit Anita Hørup Larsen (Member of study group), Ioannis Louloudis (Member of study group), Agnete Lundgaard (Member of study group), Susan Mikkelsen (Member of study group), Christina Mikkelsen (Member of study group), Ioanna Nissen (Member of study group), Mette Nyegaard (Member of study group), Ole Birger Pedersen (Member of study group), Alexander Pil Henriksen (Member of study group), Palle Duun Rohde (Member of study group), Klaus Rostgaard (Member of study group), Michael Schwinn (Member of study group), Hreinn Stefansson (Member of study group), Erik Sørensen (Member of study group), Unnur Þorsteinsdóttir (Member of study group), Lise Wegner Thørner (Member of study group), Mie Topholm Bruun (Member of study group), Henrik Ullum (Member of study group), Thomas Werge (Member of study group), David Westergaard (Member of study group), Jan Haavik, Ole A. Andreassen, David Rye, Jannicke Igland, Sisse Rye Ostrowski, Lili A. Milani, Lincoln D. Nadauld, Hreinn Stefansson, Kari Stefansson

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Abstract

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson’s disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Original language	English
Article number	504
Journal	Communications Biology
Volume	7
Issue number	1
Pages (from-to)	504
Number of pages	1
ISSN	2399-3642
DOIs	https://doi.org/10.1038/s42003-024-06207-4
Publication status	Published - 26 Apr 2024

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Skuladottir, A. T., Stefansdottir, L., Halldorsson, G. H., Stefansson, O. A., Bjornsdottir, A., Jonsson, P., Palmadottir, V., Thorgeirsson, T. E., Walters, G. B., Gisladottir, R. S., Bjornsdottir, G., Jonsdottir, G. A., Sulem, P., Gudbjartsson, D. F., Knowlton, K. U., Jones, D. A., Ottas, A., Esko, T., Mägi, R., ... Stefansson, K. (2024). GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis. Communications Biology, 7(1), 504. Article 504. https://doi.org/10.1038/s42003-024-06207-4

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title = "GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis",

abstract = "Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson{\textquoteright}s disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.",

author = "Skuladottir, {Astros Th.} and Lilja Stefansdottir and Halldorsson, {Gisli H.} and Stefansson, {Olafur A.} and Anna Bjornsdottir and Palmi Jonsson and Vala Palmadottir and Thorgeirsson, {Thorgeir E.} and Walters, {G. Bragi} and Gisladottir, {Rosa S.} and Gyda Bjornsdottir and Jonsdottir, {Gudrun A.} and Patrick Sulem and Gudbjartsson, {Daniel F.} and Knowlton, {Kirk U.} and Jones, {David A.} and Aigar Ottas and T{\~o}nu Esko and Reedik M{\"a}gi and Mari Nelis and Georgi Hudjashov and Pedersen, {Ole B.} and Maria Didriksen and S{\o}ren Brunak and Karina Banasik and Hansen, {Thomas Folkmann} and Christian Erikstrup and {DBDS Genomic Consortium} and Jakob Bay and Boldsen, {Jens Kj{\ae}rgaard} and Thorsten Brodersen and Kristoffer Burgdorf and Chalmer, {Mona Ameri} and Dinh, {Khoa Manh} and Joseph Dowsett and Bjarke Feenstra and Frank Geller and Daniel Gudbjartsson and Lotte Hindhede and Henrik Hjalgrim and Jacobsen, {Rikke Louise} and Gregor Jemec and Jensen, {Bitten Aagaard} and Katrine Kaspersen and Kjerulff, {Bertram Dalskov} and Lisette Kogelman and Larsen, {Margit Anita H{\o}rup} and Ioannis Louloudis and Agnete Lundgaard and Susan Mikkelsen and Christina Mikkelsen and Ioanna Nissen and Mette Nyegaard and Pedersen, {Ole Birger} and Henriksen, {Alexander Pil} and Rohde, {Palle Duun} and Klaus Rostgaard and Michael Schwinn and Hreinn Stefansson and Erik S{\o}rensen and Unnur {\TH}orsteinsd{\'o}ttir and Th{\o}rner, {Lise Wegner} and Bruun, {Mie Topholm} and Henrik Ullum and Thomas Werge and David Westergaard and Jan Haavik and Andreassen, {Ole A.} and David Rye and Jannicke Igland and Ostrowski, {Sisse Rye} and Milani, {Lili A.} and Nadauld, {Lincoln D.} and Hreinn Stefansson and Kari Stefansson",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = apr,

day = "26",

doi = "10.1038/s42003-024-06207-4",

language = "English",

volume = "7",

pages = "504",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Nature Publishing Group",

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Skuladottir, AT, Stefansdottir, L, Halldorsson, GH, Stefansson, OA, Bjornsdottir, A, Jonsson, P, Palmadottir, V, Thorgeirsson, TE, Walters, GB, Gisladottir, RS, Bjornsdottir, G, Jonsdottir, GA, Sulem, P, Gudbjartsson, DF, Knowlton, KU, Jones, DA, Ottas, A, Esko, T, Mägi, R, Nelis, M, Hudjashov, G, Pedersen, OB, Didriksen, M, Brunak, S, Banasik, K, Hansen, TF, Erikstrup, C, DBDS Genomic Consortium, Bay, J, Boldsen, JK, Brodersen, T, Burgdorf, K, Chalmer, MA, Dinh, KM, Dowsett, J, Feenstra, B, Geller, F, Gudbjartsson, D, Hindhede, L, Hjalgrim, H, Jacobsen, RL, Jemec, G, Jensen, BA, Kaspersen, K, Kjerulff, BD, Kogelman, L, Larsen, MAH, Louloudis, I, Lundgaard, A, Mikkelsen, S, Mikkelsen, C, Nissen, I, Nyegaard, M, Pedersen, OB, Henriksen, AP, Rohde, PD, Rostgaard, K, Schwinn, M, Stefansson, H, Sørensen, E, Þorsteinsdóttir, U, Thørner, LW, Bruun, MT, Ullum, H, Werge, T, Westergaard, D, Haavik, J, Andreassen, OA, Rye, D, Igland, J, Ostrowski, SR, Milani, LA, Nadauld, LD, Stefansson, H & Stefansson, K 2024, 'GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis', Communications Biology, vol. 7, no. 1, 504, pp. 504. https://doi.org/10.1038/s42003-024-06207-4

TY - JOUR

T1 - GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis

AU - Skuladottir, Astros Th.

AU - Stefansdottir, Lilja

AU - Halldorsson, Gisli H.

AU - Stefansson, Olafur A.

AU - Bjornsdottir, Anna

AU - Jonsson, Palmi

AU - Palmadottir, Vala

AU - Thorgeirsson, Thorgeir E.

AU - Walters, G. Bragi

AU - Gisladottir, Rosa S.

AU - Bjornsdottir, Gyda

AU - Jonsdottir, Gudrun A.

AU - Sulem, Patrick

AU - Gudbjartsson, Daniel F.

AU - Knowlton, Kirk U.

AU - Jones, David A.

AU - Ottas, Aigar

AU - Esko, Tõnu

AU - Mägi, Reedik

AU - Nelis, Mari

AU - Hudjashov, Georgi

AU - Pedersen, Ole B.

AU - Didriksen, Maria

AU - Brunak, Søren

AU - Banasik, Karina

AU - Hansen, Thomas Folkmann

AU - Erikstrup, Christian

AU - DBDS Genomic Consortium

AU - Kogelman, Lisette

AU - Haavik, Jan

AU - Andreassen, Ole A.

AU - Rye, David

AU - Igland, Jannicke

AU - Ostrowski, Sisse Rye

AU - Milani, Lili A.

AU - Nadauld, Lincoln D.

AU - Stefansson, Hreinn

AU - Stefansson, Kari

A2 - Bay, Jakob

A2 - Boldsen, Jens Kjærgaard

A2 - Brodersen, Thorsten

A2 - Burgdorf, Kristoffer

A2 - Chalmer, Mona Ameri

A2 - Dinh, Khoa Manh

A2 - Dowsett, Joseph

A2 - Feenstra, Bjarke

A2 - Geller, Frank

A2 - Gudbjartsson, Daniel

A2 - Hindhede, Lotte

A2 - Hjalgrim, Henrik

A2 - Jacobsen, Rikke Louise

A2 - Jemec, Gregor

A2 - Jensen, Bitten Aagaard

A2 - Kaspersen, Katrine

A2 - Kjerulff, Bertram Dalskov

A2 - Larsen, Margit Anita Hørup

A2 - Louloudis, Ioannis

A2 - Lundgaard, Agnete

A2 - Mikkelsen, Susan

A2 - Mikkelsen, Christina

A2 - Nissen, Ioanna

A2 - Nyegaard, Mette

A2 - Pedersen, Ole Birger

A2 - Henriksen, Alexander Pil

A2 - Rohde, Palle Duun

A2 - Rostgaard, Klaus

A2 - Schwinn, Michael

A2 - Stefansson, Hreinn

A2 - Sørensen, Erik

A2 - Þorsteinsdóttir, Unnur

A2 - Thørner, Lise Wegner

A2 - Bruun, Mie Topholm

A2 - Ullum, Henrik

A2 - Werge, Thomas

A2 - Westergaard, David

PY - 2024/4/26

Y1 - 2024/4/26

N2 - Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson’s disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

AB - Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson’s disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

U2 - 10.1038/s42003-024-06207-4

DO - 10.1038/s42003-024-06207-4

M3 - Journal article

C2 - 38671141

SN - 2399-3642

VL - 7

SP - 504

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 504

ER -

GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis

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