American Journal of Medical Genetics (Neuropsychiatric Genetics) zyx 60:94-102 (1995) Linkage Studies of Bipolar Disorder in the Region of the Darier’s Disease Gene on Chromosome 12q23-24.1 Elisabeth Dawson, Elizabeth Parfitt, Queta Roberts, Jo Daniels, Lionel Lim, Pak Sham, Markus Nothen, Peter Propping, Mario Lanczik, Wolfgang Maier, Ulrike Reuner, Jean Weissenbach, Michael Gill, John Powell, Peter McGuffin, Mike Owen, and Nick Craddock zyxw Department zyxwvutsrqp of Psychological Medicine (E.P., Q.R., J.D., P.M., M.O., N.C.), Department of Medical Genetics (E.P., Q.R., J.D., M.O.), University of Wales College of Medicine, Heath Park, Cardifi Departments of Neuroscience and Psycho- logical Medicine, Institute of Psychiatry (E.D., L.L., P.S., M.G., J.P.), London, United Kingdom; Institute of Human Genetics, University of Bonn (M.N., P.P.), Bonn, Psychiatric Clinic, University of Wiirzburg (M.L.), Wiirzburg, Psychi- atric Clinic, University of Mainz (W.M.), Mainz, Psychiatric Clinic, Medical Academy (U.R.), Dresden, Germany; GenB thon (J. W.), Evry, France; Department of Psychological Medicine, National University of Singapore (L.L.), Singapore; and Department of Psychiatry, Washington University School of Medicine, Jewish Hospital (N.C.), St Louis, Missouri We have recently described a family in which there is cosegregation of major affec- tive disorder with Darier’s disease and have mapped this autosomal dominant skin dis- order to 12q23-q24.1. This has provided an interesting candidate region for genetic studies of bipolar disorder. We have studied the segregation of seven markers spanning the Darier’s disease locus in zyxwvu 45 bipolar dis- order pedigrees and found modest evidence in support of linkage under heterogeneity for zyxwvuts 5 of these markers. Nonparametric analyses were suggestive of linkage with a marker at the gene encoding a secretory form of phospholipase zyxwvu A2. Our sample has relatively low power to detect linkage under heterogeneity and independent researchers should examine markers from this region in further samples of bipolar pedigrees. zyxwv 0 1995 Wiley-Liss, Inc. KEY WORDS: affective disorder, candidate gene, DAR locus, PLA2 INTRODUCTION There is compelling evidence from family, twin and adoption studies for the existence of important genetic factors determining susceptibility to bipolar affective Received for publication January 3, 1994; revision received March 4, 1994. Address reprint requests to Drs. Nick Craddock and Mike Owen, Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, United Kmgdom. 0 1995 Wiley-Liss, Inc. disorder [Craddock and McGuffin, 19931. However, the mode of inheritance is unknown. Simple mendelian transmission may occur in some families but cannot ex- plain the majority of cases [Sham et al., 19921, which probably reflect the action of several genes together with environmental factors. With the advent of poly- morphic DNA markers, linkage and association studies have become potentially useful methods for genetic analysis of affective illness, but as yet, no consistent findings have emerged. An important problem in molecular genetic studies is deciding where in the genome to look for susceptibility loci. A random or systematic “genome search” may ulti- mately prove necessary but the more focused approach of examining “candidate” regions may be particularly efficient. A region can be considered a “candidate” if there exists some a priori evidence that a susceptibility locus may be located within it. This evidence may come from: (1) knowledge that a gene encoding an enzyme or structural protein thought to be important in the pathogenesis of affective disorder lies within the region [e.g., Leboyer et al., 19901, (2) the discovery of cytoge- netic abnormalities associated with bipolar disorder [Craddock and Owen, 19941, and (3) the finding of cosegregation within families of bipolar disorder and a monogenic disorder. Such an observed cosegregation formed the rationale for this study. If bipolar disorder and a disease (or trait) determined by a single gene are associated within families, there are a number of possible causes for this: (1) the two dis- orders are different manifestations of the same genetic defect (pleiotropy), (2) they are caused by defects in genes close enough together on the same chromosome to display linkage, and (3) they could be part of a con- tiguous deletion syndrome, the chromosomal deletion being too small to be detectable by routine cytogenetic methods.