Partitioning the genetic architecture of amyotrophic lateral sclerosis
Partitioning the genetic architecture of amyotrophic lateral sclerosis
ABSTRACT The genetic basis of sporadic amyotrophic lateral sclerosis (ALS) is not well understood. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) associated with ALS conditional on genetic data from 65 different traits and diseases from >3 million people. We found strong genetic enrichment between ALS and a number of disparate traits including frontotemporal dementia, coronary artery disease, C-reactive protein, celiac disease and memory function. Beyond C9ORF72, we detected novel genetic signal within numerous loci including GIPC1, ELMO1 and COL16A and confirmed previously reported variants, such as ATXN2, KIF5A, UNC13A and MOBP. We found that ALS variants form a small-world co-expression network characterized by highly inter-connected ‘hub’ genes. This network clustered into smaller sub-networks, each with a unique function. Altered gene expression of several sub-networks and hubs was over-represented in neuropathological samples from ALS patients and SOD1 G93A mice. Our collective findings indicate that the genetic architecture of ALS can be partitioned into distinct components where some genes are highly important for developing disease. These findings have implications for stratification and enrichment strategies for ALS clinical trials.
Andreassen Ole A.、Kao Aimee、Olney Nicholas T.、Finkbeiner Steve、Atassi Nazem、Veldink Jan H.、Dale Anders M.、Karch Celeste M.、Broce Iris J.、Lomen-Hoerth Catherine、Fan Chun C.、van Rheenen Wouter、Seeley William W.、Yokoyama Jennifer S.、Sugrue Leo P.、Cudkowicz Merit E.、Dillon William P.、Desikan Rahul S.、Hess Christopher P.、Miller Bruce L.、Al-Chalabi Ammar、Glastonbury Christine M.
Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of OsloDepartment of Neurology, University of CaliforniaDepartment of Neurology, University of CaliforniaDepartment of Neurology, University of CaliforniaDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Center UtrechtDepartment of Cognitive Sciences, University of California||Department of Radiology, University of California||Department of Neurosciences, University of CaliforniaDepartment of Psychiatry, Washington University in St LouisDepartment of Radiology and Biomedical Imaging, University of CaliforniaDepartment of Neurology, University of CaliforniaDepartment of Cognitive Sciences, University of CaliforniaDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Center UtrechtDepartment of Neurology, University of CaliforniaDepartment of Neurology, University of CaliforniaDepartment of Radiology and Biomedical Imaging, University of CaliforniaDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Radiology and Biomedical Imaging, University of CaliforniaDepartment of Radiology and Biomedical Imaging, University of CaliforniaDepartment of Radiology and Biomedical Imaging, University of CaliforniaDepartment of Neurology, University of CaliforniaKing?ˉs College London, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience and Department of Neurology, King?ˉs College HospitalDepartment of Radiology and Biomedical Imaging, University of California
神经病学、精神病学遗传学基础医学
Andreassen Ole A.,Kao Aimee,Olney Nicholas T.,Finkbeiner Steve,Atassi Nazem,Veldink Jan H.,Dale Anders M.,Karch Celeste M.,Broce Iris J.,Lomen-Hoerth Catherine,Fan Chun C.,van Rheenen Wouter,Seeley William W.,Yokoyama Jennifer S.,Sugrue Leo P.,Cudkowicz Merit E.,Dillon William P.,Desikan Rahul S.,Hess Christopher P.,Miller Bruce L.,Al-Chalabi Ammar,Glastonbury Christine M..Partitioning the genetic architecture of amyotrophic lateral sclerosis[EB/OL].(2025-03-28)[2025-05-21].https://www.biorxiv.org/content/10.1101/505693.点此复制
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