Genome-scan for bipolar disorder with sib-pair families in the Sardinian population: a new susceptibility locus on chromosome 1p22-p21?

The discovery of the genetic factors implicated in the predisposition to complex diseases may greatly profit from genetic studies in isolated populations. In this perspective, we performed a genome-wide scan using 507 microsatellite markers, with an average interval size of 7.6 cM, on a sample of 88 nuclear families with at least two affected sibs with bipolar disorder recruited in the Sardinian population. An initial analysis yielded non-parametric linkage exceeding 3.4 with P-values <0.0003 at two adjacent markers, D1S206 and D1S435 in the 1p22-p21 chromosomal region. Moreover, positive linkage ranging between 2.0 and 3.0 was obtained for other loci in several cases in regions that have already been linked to predisposition to bipolar disorder, such as 5p15.33, 8q24.13, and 11q14.3. A subsequent analysis of the 1p22-p21 region using the same set of families and a dense panel of 20 new microsatellite markers, spaced at 1.2 cM on average, reinforced the finding of suggestive linkage for this region. Interestingly, NPL values above 2.1 and P-values <0.02 were obtained for a cluster of 10 markers comprising D1S435. Thus, this study suggests that the 1p22-p21 region may contain a new locus participating to the genetic susceptibility to bipolar disorder and reproduces positive linkage for several other loci already implicated in this pathology. Since the Sardinian population presents a peculiar genetic homogeneity, these results may pave the way to further studies for replication in this population contributing to the rapid discovery of the genetic factors predisposing to bipolar disorder.

No replication of genetic association between candidate polymorphisms and Alzheimer's disease.

Alzheimer's disease is a genetically complex disorder, for which new putative susceptibility genes are constantly proposed in the literature. We selected 16 candidate genes involved in biological pathways closely related to the pathology, and for which a genetic association with Alzheimer's disease was previously detected: ACE, BACE1, BDNF, ECE1, HSPG2, IDE, IL1a, IL6, IL10, MAPT, PLAU, PrnP, PSEN1, SORL1, TFCP2 and TGFb1. The variants originally associated with the disease were genotyped in a French Caucasian sample including 428 cases and 475 controls and tested for association in order to replicate the initial results. Despite a careful replication study design, we failed to validate the initial findings for any of these variants, with the possible exception of MAPT, SORL1 and TFCP2 for which some nominal but inconsistent evidence of association was observed.