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

Abstract

Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and/or hypomania interspersed with periods of depression. Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD. To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing 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 extremely high incidence of BPAD. We have found strong evidence for a locus on chromosome 4p at D4S2949 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4.05, P = 5. 22 x 10(-4); SIBPAL Pempirical value <3 x 10(-5)) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score = 3.29, P = 2.57 x 10(-3); SIBPAL Pempirical value <1 x 10(-3)) that are linked to mental health wellness. These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders.

Figure 1

Plot of test statistics obtained from the pair-wise linkage results. (Inset) A cumulative plot of P-values whose linearity would reflect uniformity in P-values associated with multiple linkage results whose null hypotheses were all true (see text). The outlying test statistics and P-values (denoted by arrows) were associated with markers, D4S107 (t = 6.24), D4S2949 (t = 7.79), D4S2928 (t = 5.03), D11S133 (t = 6.09), and D11S29 (t = 6.32).

Figure 2

Model-free linkage analysis of wellness by using GH-PLUS. Map position is in Kosambi centimorgans. The −log₁₀ P was calculated by using P values generated by GH-PLUS on the assumption that the NPL score is standard normally distributed. A −log₁₀ P of 4.0 corresponds asymptotically to a logarithm of odds score of 3.0. Only mentally healthy individuals 45 years of age or older were classified as being well (see text). (A) −log₁₀ P for markers on chromosome 4p: dotted line, pedigree 110 only; and solid line, pedigrees 110, 210, 310, and 410. (B) −log₁₀ P for markers on chromosome 4q: dotted line, pedigree 110 only, and solid line, pedigrees 110, 210, 310, and 410.