Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium

Abstract

Genetic mapping studies in bipolar disorder (BD) have been hampered by the unclear boundaries of the phenotypic spectrum, and possibly, by the complexity of the underlying genetic mechanisms, and heterogeneity. Among the suggested approaches to circumvent these problems, a pharmacogenetic strategy has been increasingly proposed. Several studies have indicated that patients with BD who respond well to lithium prophylaxis constitute a biologically distinct subgroup. In this study we have conducted a complete genome scan using 378 markers spaced at an average distance of 10 cM in 31 families ascertained through excellent lithium responders. Response to lithium was evaluated prospectively with an average follow-up of 12 years. Evidence for linkage was found with a locus on chromosome 15q14 (ACTC, lod score = 3.46, locus-specific P-value = 0.000014) and suggestive results were observed for another marker on chromosome 7q11.2 (D7S1816, lod score = 2.68, locus-specific P-value = 0.00011). Other interesting findings were obtained with markers on chromosomes 6 and 22, namely D6S1050 (lod score = 2.0, locus-specific P-value = 0.00004) and D22S420 (lod score = 1.91). Nonparametric linkage analysis provided additional support for the role of these loci. Further analyses of these results suggested that the locus on chromosome 15q14 may be implicated in the etiology of BD, whereas the 7q11.2 locus may be relevant for lithium response. In conclusion, our results provide original evidence suggesting that loci on 15q14 and 7q11.2 may be implicated in the pathogenesis of BD responsive to lithium. Molecular Psychiatry (2001) 6, 570-578.

The phenotypes of bipolar disorder: relevance for genetic investigations

“…99 These findings indicate that the subgroup of patients with BDII, comorbid panic disorder, and mood lability may share a susceptibility gene on the long arm of chromosome 18q, with a possible parent-of-origin effect. In family studies of lithium-responsive probands, we found little evidence of linkage to chromosome 18 markers, 100,101 which is consistent with the observation of very low rates of comorbid conditions and mood lability among responders to lithium. 102 Such traits, on the other hand, are common among responders to the anticonvulsant lamotrigine.…”

“…135 Nonaffective psychiatric disorders among relatives of lithium responders are uncommon. [101][102][103] Treatment outcome findings in BD also define lithium responders as a distinct, more uniform subgroup. Responders to lithium differ from responders to other mood stabilizers and the treatment response appears to be specific; 103,[136][137][138][139] the antimanic responses to valproate and lithium are present in different patient groups.…”

Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families

“…55 As also shown in Table 3, a significant linkage has also been reported in BP probands with a good response to lithium and their relatives affected by either BP, recurrent major depression or SZA. 56 It is difficult to interpret, at this moment, whether there is one or several susceptibility genes in 15q11, for SZ, BP or both (Table 3).…”

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

“…The P50 sensory gating deficit, one of the best supported endophenotypes of schizophrenia and bipolar disorder, is strongly linked to this region, 1 as are two idiopathic epilepsies. 2,3 Of the many attempts to demonstrate linkage of schizophrenia and bipolar disorder to this region, two studies showed linkage to bipolar disorder, 4,5 but several found either weak [6][7][8][9][10] or no linkage to schizophrenia. [11][12][13] Both schizophrenia and bipolar disorder have also shown association with 15q13.3 markers.…”