We report the first stage of a genome scan of schizophrenia (SZ) and bipolar disorder (BP) covering 18 candidate chromosomal areas. In addition to testing susceptibility loci that are specific to each disorder, we tested the hypothesis that some susceptibility loci might be common to both disorders. A total of 480 individuals from 21 multigenerational pedigrees of Eastern Qué bec were evaluated by means of a consensus best-estimate diagnosis made blind to diagnoses in relatives and were genotyped with 220 microsatellite markers. Two-point and multipoint model-based linkage analyses were performed and mod scores (Z, for max Z max ) are reported. The strongest linkage signals were detected at D18S1145 (in 18q12; Z = 4.03) for BP, and at D6S334 (in 6p 22-24; Z het = 3.47; ␣ = 0.66) for SZ. Three other chromosomal areas (3q, 10p, and 21q) yielded linkage signals. Chromosomes 3p, 4p, 5p, 5q, 6q, 8p, 9q, 11q, 11p, 12q, 13q, 18p and 22q showed no evidence of linkage. The 18q12 results met the Lander and Kruglyak (1995) criterion for a genome-wide significant linkage and suggested that this susceptibility region may be shared by SZ and BP. The 6p finding provided confirmatory evidence of linkage for SZ. Our results suggest that both specific and common susceptibility loci must be searched for SZ and BP. Molecular Psychiatry (2001) 6, 684-693.Keywords: schizophrenia; bipolar disorder; linkage analysis; psychiatric genetics; family studies Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable disorders probably involving several genes and environmental factors. 1-3 Although previous linkage studies have yielded promising results for both disorders 4-6 (see Riley and McGuffin 7 and Pulver 8 for a recent comprehensive review), their results are often conflicting and difficult to interpret. Methodological obstacles to definitive findings include insufficient statistical power, unknown mode of inheritance, populational differences, uncertain phenotype definitions, 3,9 which also complicate the comparison of results across studies. In addition, studies suggested that some susceptibility loci such as 13q32 5,6 and 18p11 5,10 might be common to both disorders. 11,12 As discussed elsewhere, 2,13,14 such common loci are compatible with previous reports of some degree of coaggregation between SZ and mood disorders. 15 In this context, as a first stage of a genome scan for SZ and BP, we prioritized chromosomal areas based on previous linkage or association results before using, in the second stage, evenly spaced (7-10 cM) markers to cover the rest of the genome which is underway. Our criteria to select candidate areas were based on previous findings of a lod score of at least 2 in the case of parametric (model-based) analyses, or a P-value of at least 0.005 in the case of non-parametric (model-free) analyses. Two other regions were investigated as follow-ups of our own preliminary findings suggesting an association between adult onset SZ and the DRD3 locus 14 and of a suggestive linkage between SZ and 11q21-q24. 16 We r...

Recent reports of a linkage trend in 6p24-22 for schizophrenia (SZ), in different samples, were tempered by the concurrent evidence of negative reports in other samples. In the studies showing positive results, different definitions of affection and a wide spectrum of diagnoses were used. Our objectives were not only to test for linkage at 6p24-22 in the Eastern Quebec population, but also to test whether this putative vulnerability locus was either selectively linked to schizophrenia (SZ), or to bipolar disorder (BP), or to both major psychoses. Parametric and nonparametric linkage analyses with 12 microsatellite markers in 6p24-p22 were performed on a sample of 18 large multigenerational pedigrees (N = 354) either affected by SZ, or by BP, or equally affected by both major psychoses (i.e., mixed pedigrees). Three affection definitions were usually tested in our program: one on schizophrenia (SZ), one on bipolar disorder (BP), and one that comprised SZ and BP under the hypothesis of a susceptibility locus common to both in major psychoses (common locus, CL). The results of parametric analyses did not support a major gene hypothesis. However, in one large mixed pedigree (#151), we observed with the common locus phenotype (CL) lod scores of 2.49 and 2.15, respectively, at the D6S296 and D6S277 loci under a dominant model. Our data suggest the presence of a potential vulnerability locus at 6p24-22 that could be related to both schizophrenia and bipolar affective disorder. These results may be seen as congruent with former studies that used schizoaffective as well as schizophrenia diagnoses as entry criteria for the affected families, and used an affection definition that comprised affective psychoses as well as schizophrenia.

Recent reports of a linkage trend in 6p24-22 for schizophrenia (SZ), in different samples, were tempered by the concurrent evidence of negative reports in other samples. In the studies showing positive results, different definitions of affection and a wide spectrum of diagnoses were used. Our objectives were not only to test for linkage at 6p24-22 in the Eastern Quebec population, but also to test whether this putative vulnerability locus was either selectively linked to schizophrenia (SZ), or to bipolar disorder (BP), or to both major psychoses. Parametric and nonparametric linkage analyses with 12 microsatellite markers in 6p24-p22 were performed on a sample of 18 large multigenerational pedigrees (N = 354) either affected by SZ, or by BP, or equally affected by both major psychoses (i.e., mixed pedigrees). Three affection definitions were usually tested in our program: one on schizophrenia (SZ), one on bipolar disorder (BP), and one that comprised SZ and BP under the hypothesis of a susceptibility locus common to both in major psychoses (common locus, CL). The results of parametric analyses did not support a major gene hypothesis. However, in one large mixed pedigree (#151), we observed with the common locus phenotype (CL) lod scores of 2.49 and 2.15, respectively, at the D6S296 and D6S277 loci under a dominant model. Our data suggest the presence of a potential vulnerability locus at 6p24-22 that could be related to both schizophrenia and bipolar affective disorder. These results may be seen as congruent with former studies that used schizoaffective as well as schizophrenia diagnoses as entry criteria for the affected families, and used an affection definition that comprised affective psychoses as well as schizophrenia.

No abstract

We have performed initial nonparametric sib‐pair genome scans in the early (N = 52) and late (N = 53) onset subgroups of the COGA pedigrees, stratified near the median value of pedigree mean age of onset for ALDX1 diagnosis of alcoholism. Because the early group contained a higher proportion of smokers, traits of alcoholism, smoking, and addiction (defined as either alcoholism or smoking) were examined. Subgroups and phenotypic definitions influenced initial linkage results, corrected for the number of analyzed traits. Evidence for linkage to the ALDX1 alcoholism phenotype at the ADH3 functional candidate gene was increased in the late onset subgroup (Bonferroni corrected significance level < 0.002), as compared with the unstratified sample that replicated COGA linkage obtained in the same analysis; there was no evidence for linkage at this locus in the early onset subgroup. The theoretical implication of this result is that the loss of power due to contracting sample size through stratification may in some cases be more than offset by extraction of a more homogenous subgroup from the etiologically complex trait.