Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis - Archive ouverte HAL Access content directly
Journal Articles Annals of Neurology Year : 2019

Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

(1, 2) , (3, 4) , (5) , , , , , , , (6) , (7) , , , , (8) , , , , , , , , , (9) , , (10) , (11) , , (12) , , , , (13) , , , , (14) , (15) , , , , , , , , (16) , , , (17) , (18) , , , (7) , , (19) , , , , , , , , , , (20) , (21) , , , , (22) , (23) , , , , , , , (17) , , , , (24) , , (25) , , (26) , , (27) , (28) , (29) , (30) , , , (19) , (31) , , (32) , , , , , , , , , (33) , , (34) , (35) , (36) , , (37) , , , , (38) , , (14) , (39) , (40) , , , (40) , , , , , , , , , , (41) , , , , (42) , , (43) , (44) , , (45) , , , (46) , (47) , (48) , (49) , (50) , (48) , (50) , , (51) , (52) , (53) , (54) , (7) , (55) , (56)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
Alessandro Arosio
  • Function : Author
Marco Barberis
  • Function : Author
Ilaria Bartolomei
  • Function : Author
Stefania Battistini
  • Function : Author
Michele Benigni
  • Function : Author
Giuseppe Borghero
  • Function : Author
Stefania Cammarosano
  • Function : Author
Antonino Cannas
  • Function : Author
Antonio Canosa
  • Function : Author
Margherita Capasso
  • Function : Author
  • PersonId : 897084
Claudia Caponnetto
  • Function : Author
Carla Caredda
  • Function : Author
Paola Carrera
  • Function : Author
Federico Casale
  • Function : Author
Sebastiano Cavallaro
  • Function : Author
Tiziana Colletti
  • Function : Author
Francesca Conforti
  • Function : Author
Amelia Conte
  • Function : Author
Emanuela Costantino
  • Function : Author
Antonio Fasano
  • Function : Author
  • PersonId : 890474
Cinzia Femiano
  • Function : Author
Nicola Fini
  • Function : Author
Gianluca Floris
  • Function : Author
Giuseppe Fuda
  • Function : Author
Maurizio Grassano
  • Function : Author
Antonio Ilardi
  • Function : Author
Vincenzo La Bella
  • Function : Author
Francesco Logullo
  • Function : Author
Daniela Loi
  • Function : Author
Christian Lunetta
  • Function : Author
Gianluigi Mancardi
  • Function : Author
Paola Mandich
  • Function : Author
Jessica Mandrioli
  • Function : Author
Umberto Manera
  • Function : Author
Kalliopi Marinou
  • Function : Author
Giuseppe Marrali
  • Function : Author
Letizia Mazzini
  • Function : Author
  • PersonId : 910160
Maurizio Melis
  • Function : Author
Sonia Messina
  • Function : Author
Maria Rosaria Monsurro
  • Function : Author
Lorena Mosca
  • Function : Author
Patrizia Occhineri
  • Function : Author
Paola Origone
  • Function : Author
Carla Pani
  • Function : Author
Silvana Penco
  • Function : Author
Antonio Petrucci
  • Function : Author
Giovanni Piccirillo
  • Function : Author
Angelo Pirisi
  • Function : Author
Fabrizio Pisano
  • Function : Author
Claudia Ricci
  • Function : Author
Maria Rita Murru
  • Function : Author
Nilo Riva
  • Function : Author
Marialuisa Santarelli
  • Function : Author
Riccardo Sideri
  • Function : Author
Isabella Simone
  • Function : Author
Rossella Spataro
  • Function : Author
Raffaella Tanel
  • Function : Author
Gioacchino Tedeschi
  • Function : Author
Lucio Tremolizzo
  • Function : Author
Francesca Trojsi
Paolo Volanti
  • Function : Author
Marcella Zollino
  • Function : Author
  • PersonId : 902063
Yevgeniya Abramzon
  • Function : Author
Robert Baloh
  • Function : Author
Christopher Brady
  • Function : Author
Ruth Chia
  • Function : Author
John Cooper‐knock
  • Function : Author
Carsten Drepper
  • Function : Author
Travis Dunckley
  • Function : Author
John Eicher
  • Function : Author
Faraz Faghri
  • Function : Author
Eva Feldman
  • Function : Author
Mary Kay Floeter
  • Function : Author
Pietro Fratta
  • Function : Author
Joshua Geiger
  • Function : Author
Glenn Gerhard
  • Function : Author
Summer Gibson
  • Function : Author
Terry Heiman‐patterson
  • Function : Author
Lilja Jansson
  • Function : Author
Freya Kamel
  • Function : Author
Janine Kirby
  • Function : Author
Hannu Laaksovirta
  • Function : Author
Serge Lumbroso
  • Function : Author
  • PersonId : 908759
Daniel J.L. Macgowan
  • Function : Author
Nicholas Maragakis
  • Function : Author
Kevin Mouzat
  • Function : Author
  • PersonId : 1024670
Natalie Murphy
  • Function : Author
Liisa Myllykangas
  • Function : Author
Richard Orrell
  • Function : Author
Lyle Ostrow
  • Function : Author
Roger Pamphlett
  • Function : Author
Stuart Pickering‐brown
  • Function : Author
Erik Pioro
  • Function : Author
Hannah Pliner
  • Function : Author
Stefan Pulst
  • Function : Author
Alan Renton
  • Function : Author
Alberto Rivera
  • Function : Author
Wim Robbrecht
  • Function : Author
Sara Rollinson
  • Function : Author
Sonja Scholz
  • Function : Author
Pamela Shaw
  • Function : Author
Katie Sidle
  • Function : Author
Zachary Simmons
  • Function : Author
  • PersonId : 906867
Lorne Zinman
  • Function : Author
David Stone

Abstract

To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). Methods: Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. Results: We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. Interpretation: Here, we have developed a public resource (https://lng-nia.shinyapps.io/mrshiny) which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470-481.

Dates and versions

hal-02922002 , version 1 (25-08-2020)

Identifiers

Cite

Sara Bandres‐ciga, Alastair Noyce, Gibran Hemani, Alessandro Arosio, Marco Barberis, et al.. Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis. Annals of Neurology, 2019, 85 (4), pp.470-481. ⟨10.1002/ana.25431⟩. ⟨hal-02922002⟩
30 View
0 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More