....: ~,•'~ :~ ~: ORIGINAL ARTICLES Linkage Analysis of Families with Bipolar Illness and Chromosome 18 Markers An De bruyn, Daniel Souery, Karine Mendelbaum, Julien Mendlewicz, and Christine Van Broeckhoven Linkage of bipolar (BP) illness with chromosome 18 markers located at 18pll was recently reported. A possible role for chromosome 18 in the etiology of BP illness was implicated previously by the finding in three unrelated patients of a ring chromosome with breakpoints and deleted segments at 18pter-pll and 18q23-qter. To test the potential importance of a gene defect on chromosome 18 in our material, we examined linkage with chromosome 18 markers in two families with multiple patients with BP illness or BP spectrum disorders. Fourteen simple tandem repeat polymorphisms were used located in the chromosomal region 18pll to 18q23 and separated by distances of approximately 10 cM on the genetic map. In one family linkage to chromosome 18 could not be excluded. Linkage and segregation analysis in the family suggests that the 12-cM region between D18S51 and D18S61 located at 18q21.33-q23 may contain a candidate gene for BP illness. Key Words: Bipolar illness, chromosome 18, LOD score method, segregation analysis BIOL PSYCHIATRY1996;39:679--688 Introduction The importance of genetic factors contributing to the etiology of bipolar (BP) illness is suggested by twin, family, and adoption studies (Tsuang and Faraone 1990). Two types of BP illness have been described: type I BP illness (BPI), characterized by major depressive episodes alternating with phases of mania and type II BP illness (BPII), characterized by major depressive episodes alter- From the Neurogenetics Laboratory, Born Bunge Foundation, Department of Biochemistry, University of Antwerp (UIA), Antwerp (ADB, CVB), and Division of Psychiatry, Erasme Hospital, University of Brussels (ULB), Brussels (DS, KM, JM), Belgium. Address reprint requests to Prof. Dr. C. Van Broeckhoven, PhD, Neurogenetics Laboratory, Born Bunge Foundation, University of Antwerp (UIA), Depart- ment of Biochemistry, Universiteitsplein 1, B-2610 Antwerpen, Belgium. Received October 19, 1994; revised May 4, 1995. nating with phases of hypomania. In most families of probands with BP illness patients with other BP-related disorders are also diagnosed including the manic and depressive subtypes of schizoaffective disorder (SAm, SAd); unipolar illness, recurrent (UP) and single episode (MDD); or cyclothymia (CY). Family history data indi- cated that schizoaffective and unipolar diagnoses are found more frequently among relatives of BP probands than among those of controls (Gershon et al 1982). Therefore BPI, BPII, SAm, SAd, UP, and MDD have been defined as BP spectrum disorders (Akiskal et al 1989). Although the mode of transmission of BP illness is unknown, a recent complex segregation analysis of BP families supports the existence of a single major locus (Rice et al 1987a; Spence et al 1993). In the past, multiple affected families of BP probands © 1996 Society of Biological Psychiatry 0006-3223/96/$15.00 SSDI 0006-3223(95)00293-P