Eur Psychiatry (1992) 7, 145-146 © Elsevier, Paris 145 Letter to the Editor Linkage studies of major affective disorders: the impact of the extension of pedigrees AC Bruni1'2, MP Montesi1' \ R Manfredi 2 3 , A Di C e l l o 2 3 , G Gei4, D Fragiacomo2, P De F a z i o 1 5 , M P u c a \ A Amati5, JF Foncin6 'Unit of Neurology, USSL 17; -Smid-Sud Research Center. Lamezia Terme; 'Psychiatric Care Unit, USS 17, Lainezia Terme; 4ICD-FIDIA Abano Terme; USSL 17, Smid-Sud Center, Via dei Campioni, 88046 Lamezia Terine; 'Chair of Psychiatry, Univer- sity of Reggio Calabria, School of Medicine at Catanzaro, Italy; 6Ecole Pratique des Hautes Etudes, la Salpetriere, Paris, France Strongly discordant results have been obtained so far in linkage studies of major affective disorders. Egeland el al (1987) reported preliminary evi- dence suggesting a linkage between a major locus for bipolar disorder and two markers on chromo- some 11. However, linkage with the same markers was excluded (Kelsoe el al, 1989) after the pedigree had been extended and new subjects developing the illness were assessed. Both studies were conducted with great accuracy as regards ascertainment of phenotype, laboratory techniques and statistical analysis. The authors sug- gested that the initial results may have been obtained by chance or, alternatively, that a genetic heter- ogeneity of the disease exists in the Amish popu- lation. Whatever the cause of these discrepant findings, the only way to overcome such problems is by way of an extensive epidemiological-genetic study. The direct experience of our group is enlightening in this sense. Bruni et al described in 1989 a family with a bipo- lar disorder segregating in an apparently dominant manner (fig 1): four generations of affected people, no generation skipped, male to male transmission, and an affected father, married twice, who had generated affected children from both wives. Sub- sequently, both affected and unaffected lines were extended vertically as well as horizontally, through a genealogical method called the blanket method (Foncin et al, 1988, 1989). Data on birth, marriage and death were collected from municipal archives dating back to 1809, and from parish archives dat- ing back to the 17th century. The kindred, as recon- stituted, contained not only blood relatives but also relatives by marriage and tended to be a descrip- tion of an intermarrying population. The extension of the pedigree (fig 2), with the presence of affected people in branches apparently not at risk raises doubts as to the initial evidence, generating new hypotheses of transmission related to peculiar features of the kindred, such as genetic isolation, inbreeding, apparently assortative mating. We suggest that pedigrees in which major affec- tive disorders are segregating should be submitted to a systematic investigation through this epidemi- ological genetic method, in order to clarify fun- damental issues in the psychiatric field: model(s) of transmission, effects due to environment and/or genotype, comorbidity, assortative matings and phenocopies. i . , . . 6~<5jt tJPrjrO O '! ''' ̂ 'S' ' ill : n, . . ii I? nor nt I'iK 1. Original pedigree. Subjects are identified by their pedi- gree number, Black symbols = Major affective disorders; S = Suicide or attempted suicide. 146 AC Bruni et al D- o o- T̂7> o •a D - T - O 1368 d D- 6- 61^L -ti -O 2 O-rO D- 10 111 2 3 6 6 i-n-