ORIGINAL RESEARCH ARTICLE Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22 D Lambert 1,2 , F Middle 3 , ML Hamshere 4,5 , R Segurado 1,2 , R Raybould 4 , A Corvin 1,2 , E Green 4 , E O’Mahony 1,2 , I Nikolov 4,5 , T Mulcahy 1,2 , S Haque 3 , S Bort 1,2 , P Bennett 3 , N Norton 4 , MJ Owen 4 , G Kirov 4 , C Lendon 3 , L Jones 3 , I Jones 4 , P Holmans 4,5 , M Gill 1,2 and N Craddock ,4 1 Department of Genetics, Trinity College Dublin, Dublin 2, Republic of Ireland; 2 Department of Psychiatry, Trinity College Dublin, Dublin 2, Republic of Ireland; 3 Division of Neuroscience, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Birmingham, UK; 4 Department of Psychological Medicine, The Henry Wellcome Building for Biomedical Research in Wales, Wales School of Medicine, Cardiff University, Heath Park, Cardiff, UK; 5 Biostatistics and Bioinformatics Unit, Wales School of Medicine, Cardiff University, Heath Park, Cardiff, UK Bipolar affective disorder (BPAD) is a common psychiatric disorder with complex genetic aetiology. We have undertaken a genome-wide scan in one of the largest samples of bipolar affected sibling pairs (ASPs) using a two-stage approach combining sample splitting and marker grid tightening. In this second stage analysis, we have examined 17 regions that achieved a nominally significant maximum likelihood LOD score (MLS) threshold of 0.74 (or 1.18 for the X-chromosome) in stage one. The second stage has added 135 ASP families to bring the total stage 2 sample to 395 ASPs. In total, 494 microsatellite markers have been used to screen the human genome at a density of 10 cM in the first stage sample (260 ASPs) and 5 cM in the second stage. Under the broad diagnostic model, two markers gave LOD scores exceeding 3 with two-point analysis: D4S392 (LOD ¼ 3.30) and D10S197 (LOD ¼ 3.18). Multi- point analysis demonstrated suggestive evidence of linkage between BPAD and chromosomal regions 6q16–q21 (MLS ¼ 2.61) and 4q12–q21 (MLS ¼ 2.38). 6q16–q21 is of particular interest because our data, together with those from two recent genome scans, make this the best supported linkage region in BPAD. Further, our data show evidence of a gender effect at this locus with increased sharing predominantly within the male–male pairs. Our scan also provides support for linkage (MLSZ1.5) at several other regions that have been implicated in meta-analyses of bipolar disorder and/or schizophrenia including 9p21, 10p14–p12 and 18q22. Molecular Psychiatry (2005) 10, 831–841. doi:10.1038/sj.mp.4001684; published online 17 May 2005 Keywords: genetics; genome scan; linkage; LOD score; manic-depressive; microsatellite repeats Bipolar affective disorder (Bipolar Disorder; manic depressive illness; BPAD; MIM 125480) has a lifetime prevalence of approximately 1% and is characterised by disturbances in mood ranging from extreme elation or mania to severe depression. 1 Family, twin and adoption studies provide evidence that genetic factors are important in determining susceptibility and molecular genetic studies are ongoing. 2,3 While single genes may play a major role in a few families, the inheritance of most BPAD is consistent with the action of both multiple genes and environmental factors. 4 Although the pattern of findings emerging from systematic genome screens in BPAD is consistent with there being no gene of major effect to explain the majority of cases of bipolar disorder, several regions have been implicated repeatedly as shown by meta- analyses, 5,6 including regions of 9p, 10q, 14q, 13q, 22q and chromosome 18. The linkage findings to date for bipolar disorder are less consistent than those for schizophrenia 7 and this is likely to be due, at least in part, to the substantially smaller number of families studied in bipolar disorder. 6,8 Here we present the results of a large, two-stage systematic genome scan of bipolar disorder that includes 395 affected sibling pairs (ASPs). Our study, the Wellcome Trust UK–Irish bipolar affective dis- order sibling pair genome screen, is a collaboration Received 5 January 2005; revised 4 March 2005; accepted 21 March 2005; published online 17 May 2005 Correspondence: Professor N Craddock, Department of Psycho- logical Medicine, The Henry Wellcome Building for Biomedical Research in Wales, Academic Avenue, Wales School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. E-mail: craddockn@cardiff.ac.uk Molecular Psychiatry (2005) 10, 831–841 & 2005 Nature Publishing Group All rights reserved 1359-4184/05 $30.00 www.nature.com/mp