{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T16:42:03Z","timestamp":1776876123667,"version":"3.51.2"},"posted":{"date-parts":[[2026,4,20]]},"group-title":"Genetic and Genomic Medicine","reference-count":94,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"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":[[2026,4,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Epidemiological studies show an inverse association between cigarette smoking and Parkinson\u2019s disease (PD), suggesting a potential protective effect of smoking on PD incidence, despite the well-established and overwhelming harms of smoking to human health. We integrated genomic and proteomic approaches to investigate the causality and molecular basis of this potential relationship.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed summary statistics from genome-wide association studies (GWAS) of smoking initiation (SmkInit), smoking intensity, and PD. Two-sample Mendelian randomization (MR) tested whether genetic liability to smoking behaviors causally influences PD risk. Shared genomic architecture was quantified using MiXeR, and conjunctional false discovery rate (conjFDR) analysis identified loci jointly associated with smoking and PD, which were then mapped to genes and tested for tissue enrichment. To identify mediating proteins, we integrated dorsolateral prefrontal cortex proteomic data with GWAS using proteome-wide association studies (PWAS), summary-based MR, heterogeneity in dependent instruments testing, and colocalization. Finally, the druggability of convergent genes was evaluated.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    MR analyses indicated a protective effect of genetic liability to SmkInit on PD risk (OR = 0.78, 95% CI: 0.67\u20130.91,\n                    <jats:italic>P<\/jats:italic>\n                    = 1.5 x 10\n                    <jats:sup>-3<\/jats:sup>\n                    ), which was consistent across sensitivity analyses and not suggestive of directional pleiotropy. However, no significant effect of genetic liability to cigarettes per day (CigDay) on PD risk was found. MiXeR revealed modest polygenic overlap between SmkInit and PD (13.9%; genetic correlation\n                    <jats:italic>\n                      r\n                      <jats:sub>g<\/jats:sub>\n                    <\/jats:italic>\n                    = -0.16) and between CigDay and PD (22.9%;\n                    <jats:italic>\n                      r\n                      <jats:sub>g<\/jats:sub>\n                    <\/jats:italic>\n                    = -0.09). ConjFDR identified 95 shared loci for SmkInit-PD and 26 for CigDay-PD. SmkInit-PD loci mapped to genes involved in neurotrophic signaling, synaptic organization, microglial modulation, and mitochondrial stress responses, with expression enriched in substantia nigra, basal ganglia, and interconnected cortical regions. PWAS identified 11 proteins shared by PD and SmkInit and 5 shared with CigDay, several of which (AKT3, MAPT, RIT2, EXD2, and PPP3CC) were supported by both genomic and proteomic analyses. Druggability assessment highlighted six proteins with existing pharmacologic modulation potential, spanning neurotrophic, microglial, proteostatic, and ion-channel pathways.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Genetic liability to smoking initiation appears to confer modest protection against PD. Integrative genomic and proteomic evidence converges on neurotrophic, synaptic, microglial, and mitochondrial pathways as shared mechanisms, identifying biologically coherent potential therapeutic targets for advancing smoke-free neuroprotective strategies in PD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.17.26351138","type":"posted-content","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T16:05:37Z","timestamp":1776701137000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic and Proteomic Investigation of the Smoking-Parkinson\u2019s Disease Association"],"prefix":"10.64898","author":[{"given":"Mingjian","family":"Shi","sequence":"first","affiliation":[{"name":"Uniformed Services University, Bethesda, MD 20814, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD 20817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tommy","family":"Gunawan","sequence":"additional","affiliation":[{"name":"Uniformed Services University, Bethesda, MD 20814, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD 20817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Setzer","sequence":"additional","affiliation":[{"name":"Uniformed Services University, Bethesda, MD 20814, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD 20817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Najeah","family":"Okashah","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, UC Davis, Sacramento, CA 95825, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas S.","family":"Wingo","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, UC Davis, Sacramento, CA 95825, USA"},{"name":"Alzheimer\u2019s Disease Research Center, UC Davis, Sacramento, CA 95816, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aliza P.","family":"Wingo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Services, School of Medicine, UC Davis, Sacramento, CA 95817, USA"},{"name":"Veterans Affairs Northern California Health Care System, Mather, CA 95655, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Weintraub","sequence":"additional","affiliation":[{"name":"Crescenz Veterans Affairs Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael A.","family":"Schwarzschild","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher T.","family":"Rentsch","sequence":"additional","affiliation":[{"name":"Yale School of Medicine, New Haven, CT 06511, USA"},{"name":"VA Connecticut Healthcare System, West Haven, CT 06516, USA"},{"name":"London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry R.","family":"Kranzler","sequence":"additional","affiliation":[{"name":"Crescenz Veterans Affairs Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua C.","family":"Gray","sequence":"additional","affiliation":[{"name":"Uniformed Services University, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026042208551000000_2026.04.17.26351138v1.1","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease","volume":"397","year":"2021","journal-title":"The Lancet"},{"key":"2026042208551000000_2026.04.17.26351138v1.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2401857"},{"key":"2026042208551000000_2026.04.17.26351138v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyy230"},{"key":"2026042208551000000_2026.04.17.26351138v1.4","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwm338"},{"key":"2026042208551000000_2026.04.17.26351138v1.5","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1093\/oxfordjournals.aje.a008941","article-title":"Evidence against the operation of selective mortality in explaining the association between cigarette smoking and reduced occurrence of idiopathic Parkinson disease","volume":"144","year":"1996","journal-title":"Am J Epidemiol"},{"key":"2026042208551000000_2026.04.17.26351138v1.6","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.94.15_supplement.2132"},{"key":"2026042208551000000_2026.04.17.26351138v1.7","doi-asserted-by":"crossref","first-page":"e214722","DOI":"10.1212\/WNL.0000000000214651","article-title":"Dynamic Smoking Patterns and Risk of Parkinson Disease and All-Cause Mortality","volume":"106","year":"2026","journal-title":"Neurology"},{"key":"2026042208551000000_2026.04.17.26351138v1.8","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000879"},{"key":"2026042208551000000_2026.04.17.26351138v1.9","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1093\/brain\/awad064","article-title":"Impaired dopamine release in Parkinson\u2019s disease","volume":"146","year":"2023","journal-title":"Brain"},{"key":"2026042208551000000_2026.04.17.26351138v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01429-0"},{"key":"2026042208551000000_2026.04.17.26351138v1.11","doi-asserted-by":"crossref","unstructured":"Zoli M , Pucci S , Vilella A , Gotti C . 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