{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T14:28:39Z","timestamp":1781101719127,"version":"3.54.1"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"26","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1998,12,22]]},"abstract":"<jats:p>\n                    Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and\/or hypomania interspersed with periods of depression. Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD. To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD. We have found strong evidence for a locus on chromosome 4p at\n                    <jats:italic>D4S2949<\/jats:italic>\n                    (maximum\n                    <jats:sc>genehunter-plus<\/jats:sc>\n                    nonparametric linkage score = 4.05,\n                    <jats:italic>P<\/jats:italic>\n                    = 5.22 \u00d7 10\n                    <jats:sup>\u22124<\/jats:sup>\n                    ;\n                    <jats:sc>sibpal<\/jats:sc>\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>empirical<\/jats:sub>\n                    value &lt;3 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    ) and suggestive evidence for a locus on chromosome 4q at\n                    <jats:italic>D4S397<\/jats:italic>\n                    (maximum\n                    <jats:sc>genehunter-plus<\/jats:sc>\n                    nonparametric linkage score = 3.29,\n                    <jats:italic>P<\/jats:italic>\n                    = 2.57 \u00d7 10\n                    <jats:sup>\u22123<\/jats:sup>\n                    ;\n                    <jats:sc>sibpal<\/jats:sc>\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>empirical<\/jats:sub>\n                    value &lt;1 \u00d7 10\n                    <jats:sup>\u22123<\/jats:sup>\n                    ) that are linked to mental health wellness. These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.95.26.15531","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:42:40Z","timestamp":1027680160000},"page":"15531-15536","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":68,"title":["A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish"],"prefix":"10.1073","volume":"95","author":[{"given":"Edward I.","family":"Ginns","sequence":"first","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"St. Jean","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Philibert","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzena","family":"Galdzicka","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Damschroder-Williams","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie","family":"Thiel","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Long","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loring J.","family":"Ingraham","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harnisha","family":"Dalwaldi","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"Murray","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Ehlert","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Paul","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian G.","family":"Remortel","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashima P.","family":"Patel","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C. H.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cary","family":"Shaio","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Lau","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Dymarskaia","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Martin","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Stubblefield","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Falls","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Carulli","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim P.","family":"Keith","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy S. J.","family":"Fann","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy G.","family":"Lacy","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cleona R.","family":"Allen","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abram M.","family":"Hostetter","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert C.","family":"Elston","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Schork","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice A.","family":"Egeland","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Paul","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44109; Genome Therapeutics Corporation, Waltham, MA 02154; Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, New York, NY 10467; Department of Psychiatry, University of Miami School of Medicine, Miami, FL 33136; and Departments of Psychiatry, Pharmacology, and..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1998,12,22]]},"reference":[{"key":"e_1_3_3_1_2","volume-title":"Manic-Depressive Illness","author":"Goodwin F K","year":"1990","unstructured":"F K Goodwin, K R Jamison Manic-Depressive Illness (Oxford Univ. 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