{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:10:05Z","timestamp":1792786205428,"version":"4.5.0"},"posted":{"date-parts":[[2024,7,19]]},"group-title":"Genetic and Genomic Medicine","reference-count":114,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T00:00:00Z","timestamp":1721347200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01 AA030056"],"award-info":[{"award-number":["R01 AA030056"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R35 HG011959"],"award-info":[{"award-number":["R35 HG011959"]}],"id":[{"id":"https:\/\/ror.org\/00baak391","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["UM1 DK126194"],"award-info":[{"award-number":["UM1 DK126194"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01 HD100406"],"award-info":[{"award-number":["R01 HD100406"]}],"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01 AG072705"],"award-info":[{"award-number":["R01 AG072705"]}],"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01 HD056465"],"award-info":[{"award-number":["R01 HD056465"]}],"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Mental Illness Research, Education and Clinical Center of the Crescenz VAMC","id":[{"id":"https:\/\/ror.org\/02hd1sz82","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Daniel B. Burke Endowed Chair for Diabetes Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Recent genome-wide association studies (GWAS) have revealed multiple loci for substance use disorders (SUDs), including evidence that the traits overlap in genetic etiology. However, the extent of underlying SUD causal variants, effector genes, and cellular contexts, remains unclear. Recent clinical trials of glucagon-like peptide-1 (GLP-1) receptor agonists have shown promising effects on alcohol and tobacco consumption, raising the question of whether SUD genetic risk resides in metabolic as well as neural cell types. We sought to map the cell-type-specific genetic architecture of four SUDs and to test whether the observed metabolic enrichment reflects shared causal biology with type 2 diabetes (T2D).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We integrated our 3D genomic datasets (high-resolution promoter-focused Capture-C\/Hi-C, ATAC-seq, RNA-seq) from 59 diverse human cell types with recent GWAS summary statistics for alcohol (AUD), tobacco (TUD), opioid (OUD), and cannabis use disorder (CanUD), using Stratified LD regression (S-LDSC). We performed local genetic correlation analysis (LAVA) between SUDs and T2D, multivariate integration (DIABLO) of gene expression and chromatin accessibility at shared loci, and subsequent bidirectional two-sample Mendelian randomization (MR) to test for causal relationships between T2D and each SUD.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    After per-trait false discovery rate (FDR) correction, TUD showed significant heritability enrichment in pancreatic\n                    <jats:italic>\u03b2<\/jats:italic>\n                    -cells (4.6-fold), \u03b1-cells (4.0-fold), hypothalamic neurons, and iPSC-derived neurons. CanUD showed FDR-significant enrichment concentrated in hypothalamic neural progenitor cells (7.4-fold). LAVA identified 1,550 loci with significant local genetic correlations, 114 specifically between T2D and at least one SUD. Subsequent MR revealed that genetic liability for T2D was protective against AUD (inverse-variance weighted\n                    <jats:italic>\u03b2<\/jats:italic>\n                    =-0.027,\n                    <jats:italic>P<\/jats:italic>\n                    -values = 1.6\u00d710\n                    <jats:sup>-5<\/jats:sup>\n                    , 463 instruments), consistent across four of five MR methods and free of directional pleiotropy. Cell-cell interaction modeling implicated distinct neuro-endocrine signaling axes disrupted by each SUD.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings implicate a pancreatic-SUD axis, validated by orthogonal MR evidence, that reframe SUDs as multi-system disorders, and provides a genetic-mechanistic rationale for GLP-1-based therapeutic strategies targeting addiction.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Significant Outcomes<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>Local genetic correlation analysis identifies 114 genomic loci shared between T2D and SUDs; multivariate integration at these loci reveals conserved regulatory architecture between neural and pancreatic cells operating through distinct neuro-endocrine signaling pathways.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Tobacco use disorder heritability is significantly enriched (FDR &lt; 0.05) in pancreatic \u03b1-and \u03b2-cells alongside neural lineages, establishing a multi-system genetic architecture that extends beyond the brain.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Bidirectional Mendelian randomization demonstrates that genetic liability for T2D is causally protective against alcohol use disorder (\n                        <jats:italic>P<\/jats:italic>\n                        -values = 1.6 \u00d7 10\n                        <jats:sup>-5<\/jats:sup>\n                        ), providing orthogonal validation of the pancreatic-SUD axis identified by chromatin-based enrichment.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Limitations<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>Analyses were restricted to European-ancestry GWAS; generalizability to other populations remains untested.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Ligand-receptor signaling inferences (CellChat) are computational predictions from curated databases, not experimentally validated interactions; directional claims require future\n                        <jats:italic>in vivo<\/jats:italic>\n                        confirmation.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Drug-target (cis) MR at the\n                        <jats:italic>GLP1R<\/jats:italic>\n                        locus did not reach significance for any SUD, indicating that the broader pancreatic axis \u2013 rather than GLP-1 receptor signaling alone \u2013 likely mediates the observed genetic overlap.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2024.07.18.24310649","type":"posted-content","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T15:15:17Z","timestamp":1721402117000},"source":"Crossref","is-referenced-by-count":0,"title":["Shared and unique chromatin accessibility and 3D functional interactions of substance use disorder loci implicate cell types beyond the brain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9434-508X","authenticated-orcid":false,"given":"Khanh B.","family":"Trang","sequence":"first","affiliation":[{"name":"Center 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