{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:40:13Z","timestamp":1790973613578,"version":"4.1.0"},"reference-count":83,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R25 CA092049"],"award-info":[{"award-number":["R25 CA092049"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 CA271014-01"],"award-info":[{"award-number":["U01 CA271014-01"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U01 CA257679"],"award-info":[{"award-number":["U01 CA257679"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NCI and the Mayo Clinic Cancer Center","doi-asserted-by":"publisher","award":["F99 CA234943"],"award-info":[{"award-number":["F99 CA234943"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NCI and the Mayo Clinic Cancer Center","doi-asserted-by":"publisher","award":["R01 CA107476"],"award-info":[{"award-number":["R01 CA107476"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NCI and the Mayo Clinic Cancer Center","doi-asserted-by":"publisher","award":["R01 CA168762"],"award-info":[{"award-number":["R01 CA168762"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NCI and the Mayo Clinic Cancer Center","doi-asserted-by":"publisher","award":["R25 CA092049"],"award-info":[{"award-number":["R25 CA092049"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NCI and the Mayo Clinic Cancer Center","doi-asserted-by":"publisher","award":["P50 CA186781"],"award-info":[{"award-number":["P50 CA186781"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006364","name":"French National Cancer Institute","doi-asserted-by":"publisher","award":["2010-077"],"award-info":[{"award-number":["2010-077"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondation Fran\u00e7aise pour la Recherche contre le My\u00e9lome et les Gammapathies"},{"name":"NIH Loan Repayment Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM\/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander\u2013Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r2 &lt; 0.05). Results: Significant linkage was observed at chromosome 6q22.33\u2013q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants, REPS1, THEMIS, TAAR6, AHI1, VNN1, VNN3, MTFR2\/FAM54A, LAMA2, and PHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM\/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS.<\/jats:p>","DOI":"10.3390\/cancers17223611","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T11:47:27Z","timestamp":1762775247000},"page":"3611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Whole-Exome Sequencing-Based Linkage Analysis of Multiple Myeloma (MM) and Monoclonal Gammopathy of Undetermined Significance (MGUS) Pedigrees"],"prefix":"10.3390","volume":"17","author":[{"given":"Alyssa I.","family":"Clay-Gilmour","sequence":"first","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4788-1998","authenticated-orcid":false,"given":"Nicola J.","family":"Camp","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomu","family":"Wei","sequence":"additional","affiliation":[{"name":"Weill Cornell College of Medicine, University of Cornell, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Earle","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4208-2708","authenticated-orcid":false,"given":"Aaron","family":"Norman","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1964-5522","authenticated-orcid":false,"given":"Jason","family":"Sinnwell","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Demangel","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Canc\u00e9rologie de Lyon\/Hospices Civils de Lyon, Universit\u00e9 Claude Bernard, 69373 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5721-3727","authenticated-orcid":false,"given":"Rosalie","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Cancer Cancer Prevention and Population Sciences Sciences Division, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Lymphoma & Myeloma, Cancer Medicine Division, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Dumontet","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Canc\u00e9rologie de Lyon\/Hospices Civils de Lyon, Universit\u00e9 Claude Bernard, 69373 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"McKay","sequence":"additional","affiliation":[{"name":"International Agency for Research on Cancer, World Health Organization, 69366 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2180-2032","authenticated-orcid":false,"given":"Ken","family":"Offit","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center, New York, NY 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7933-151X","authenticated-orcid":false,"given":"Vijai","family":"Joseph","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center, New York, NY 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, The University of Chicago, Chicago, NY 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health 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Cornell, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine M.","family":"Vachon","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1182\/blood-2016-09-692954","article-title":"MGUS to myeloma: A mysterious gammopathy of underexplored significance","volume":"128","author":"Dhodapkar","year":"2016","journal-title":"Blood"},{"key":"ref_2","unstructured":"Laubach, J.P. 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