A genome-wide search for chromosomal loci linked to mental health wellnessin relatives at high risk for bipolar affective disorder among the Old Order Amish

Bipolar affective disorder (BPAD; manic-depressive illness) is characterize d by episodes of mania and/or hypomania interspersed with periods of depres sion. Compelling evidence supports a significant genetic component in the s usceptibility to develop BPAD. To date, however, linkage studies have attem pted only to identify chromosomal loci that cause or increase the risk of d eveloping BPAD. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extre mely high incidence of BPAD. We have found strong evidence for a locus on c hromosome 4p at D4S2939 (maximum GENEHUNTER-PLUS nonparametric linkage scor e = 4.05, P = 5.22 x 10(-4); SIBPAL P-empirical value <3 x 10(-5)) and sugg estive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER- PLUS nonparametric linkage score 3.29, P = 2.57 x 10(-3); SIBPAL P-empirica l value <1 x 10(-3)) that are linked to mental health wellness. These findi ngs are consistent with the hypothesis that certain alleles could prevent o r modify the clinical manifestations of BPAD and perhaps other related affe ctive disorders.