{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T06:32:09Z","timestamp":1781764329780,"version":"3.54.5"},"reference-count":67,"publisher":"Canadian Science Publishing","issue":"2","license":[{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.nrcresearchpress.com\/page\/about\/CorporateTextAndDataMining"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Psychiatry Neurosci"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p> Bipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p> Overall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder\u2013manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing. We performed genome-wide linkage analysis using MERLIN and conditional linkage analysis using LAMP. We assessed the contribution of potentially functional rare variants using a gene-based segregation test. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> We identified a significant linkage peak on chromosome 10q11-q21 (maximal single nucleotide polymorphism = rs10761725; exponential logarithm of the odds [LOD<jats:sub>exp<\/jats:sub>] = 3.03; empirical p = 0.046). The linkage interval spanned 36 protein-coding genes, including a gene associated with bipolar disorder, ankyrin 3 ( ANK3). Conditional linkage analysis showed that common ANK3 risk variants previously identified in genome-wide association studies \u2014 or variants in linkage disequilibrium with those variants \u2014 did not explain the linkage signal (rs10994397 LOD = 0.63; rs9804190 LOD = 0.04). A family-based segregation test with 34 rare variants from 14 genes under the linkage interval suggested rare variant contributions of 3 brain-expressed genes: NRBF2 ( p = 0.005), PCDH15 ( p = 0.002) and ANK3 ( p = 0.014). <\/jats:p><\/jats:sec><jats:sec><jats:title>Limitations<\/jats:title><jats:p> We did not examine non-coding variants, but they may explain the remaining linkage signal. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> Combining family-based linkage analysis with next-generation sequencing data is effective for identifying putative disease genes and specific risk variants in complex disorders. We identified rare missense variants in ANK3, PCDH15 and NRBF2 that could confer disease risk, providing valuable targets for functional characterization. <\/jats:p><\/jats:sec>","DOI":"10.1503\/jpn.200083","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T16:14:52Z","timestamp":1615997692000},"page":"E247-E257","source":"Crossref","is-referenced-by-count":9,"title":["A linkage and exome study of multiplex families with bipolar disorder implicates rare coding variants of <i>ANK3<\/i> and additional rare alleles at 10q11-q21"],"prefix":"10.1139","volume":"46","author":[{"given":"Claudio","family":"Toma","sequence":"first","affiliation":[{"name":"From Neuroscience Research Australia, Sydney, Australia"},{"name":"the School of Medical Sciences, University of New South Wales, Sydney, Australia"},{"name":"the Centro de Biolog\u00eda Molecular \u2018Severo Ochoa\u2019, Universidad Aut\u00f3noma de Madrid\/CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex D.","family":"Shaw","sequence":"additional","affiliation":[{"name":"From Neuroscience Research Australia, Sydney, Australia"},{"name":"the School of Medical Sciences, University of New South Wales, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Heath","sequence":"additional","affiliation":[{"name":"From Neuroscience Research Australia, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerrie D.","family":"Pierce","sequence":"additional","affiliation":[{"name":"From Neuroscience Research Australia, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip B.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"the School of Psychiatry, University of New South Wales, Sydney, Australia"},{"name":"and the Black Dog Institute, Prince of Wales Hospital, Sydney, 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