{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T03:57:05Z","timestamp":1770263825441,"version":"3.49.0"},"posted":{"date-parts":[[2026,2,1]]},"group-title":"Genetic and Genomic Medicine","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    The\n                    <jats:italic>SLC25A46<\/jats:italic>\n                    gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in\n                    <jats:italic>SLC25A46<\/jats:italic>\n                    have been described in patients with Parkinson\u2019s disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>\n                    To assess whether\n                    <jats:italic>SLC25A46<\/jats:italic>\n                    variants contribute to PD, REM sleep behavior disorder (RBD), or Dementia with Lewy Bodies (DLB).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We examined common variants using four representative PD genome-wide association studies (GWAS) and an RBD GWAS and applied Summary-data-based Mendelian Randomization (SMR) to evaluate whether genetically regulated expression of\n                    <jats:italic>SLC25A46<\/jats:italic>\n                    shows a causal association with the risk of PD or RBD. Rare variant analyses were conducted in four cohorts of European descent: Accelerated Medicines Partnership: Parkinson\u2019s Disease (AMP-PD) PD (3,051 PD, 3,667 controls), UK Biobank (3,267 PD, 14,939 proxy, 54,800 controls), RBD (1,376 RBD, 2,580 controls), and AMP-PD DLB (2,605 DLB, 1,894 controls). Optimal Sequence Kernel Association test (SKAT-O) and meta-analysis were used to assess rare variants.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    No associations were observed between\n                    <jats:italic>SLC25A46<\/jats:italic>\n                    variants and PD, RBD, or DLB. SMR analyses revealed no evidence supporting a causal relationship between\n                    <jats:italic>SLC25A46<\/jats:italic>\n                    expression and PD or RBD risk. Rare variant burden analyses did not identify significant associations after multiple-testing correction across cohorts or meta-analyses.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    <jats:italic>SLC25A46<\/jats:italic>\n                    variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.30.26344974","type":"posted-content","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T06:00:12Z","timestamp":1770012012000},"source":"Crossref","is-referenced-by-count":0,"title":["Lack of genetic evidence for a role of SLC25A46 in alpha-synucleinopathies"],"prefix":"10.64898","author":[{"given":"Han","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Quantitative Life Science, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sitki Cem","family":"Parlar","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantin","family":"Senkevich","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma N.","family":"Somerville","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhao","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lang","family":"Liu","sequence":"additional","affiliation":[{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Human Genetics, McGill University, Montr\u00e9al, QC, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montr\u00e9al, QC, 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