No evidence of linkage between 7q33–36 locus (OTSC2) and otosclerosis in seven British Caucasian pedigrees

Background:The aetiology of otosclerosis is complex, and probably involves an interaction between genes and environmental factors. Previous studies have revealed genetic linkage with a number of chromosome regions, including position 7q33–36.Aim:To confirm whether linkage exists between otosclerosis and chromosome region 7q33–36.Materials and methods:Seven multiply affected families were ascertained. Deoxyribonucleic acid from members of these families was extracted, and six markers were genotyped to cover a 16 cM region at 7q33–36. Both parametric and non-parametric multipoint linkage analyses were performed.Results:Parametric multipoint linkage analysis excluded any linkage at 7q33–36 (logarithm of odds score <−4.0). Non-parametric linkage analysis also failed to confirm any linkage (non-parametric linkage < 1.66). When tested individually, pedigree four was the only one to show a significant non-parametric linkage score between D7s684 and D7s2513 (non-parametric linkage = 1.96).Conclusion:No linkage was detected between otosclerosis and the 7q33–36 region. This could be explained by the study's lack of power, due to the limited number of families available.

Nonparametric Linkage Analysis Between Schizophrenia and Candidate Genes of Dopaminergic and Serotonergic Systems

ABSTRACTBackground:Alterations in dopaminergic and serotonergic systems have been implicated in the pathophysiology of schizophrenia for many years. This study was performed to assess the possible involvement of the dopamine receptor genes D2 (DRD2), D3, D4, serotonin receptor genes 1Dα, 1Dβ, and 2A in the etiology of schizophrenia.Methods:We examined 33 multiplex schizophrenic families from Portugal.Results:Linkage analysis performed by GENE-HUNTER showed nonsignificant linkage for these genes. A maximum nonparametric linkage score of 1.635 (P=.032) at DRD2 gene was observed, and this finding suggests DRD2 gene for further studies.Conclusion:the polymorphisms studied at dopamine receptor genes D3, D4, serotonin receptor genes 1Dα, 1Dβ, and 2A do not have a major effect in susceptibility to schizophrenia in a Portuguese population.

Using Importance Sampling to Improve Simulation in Linkage Analysis

In this article we describe and discuss implementation of a weighted simulation procedure, importance sampling, in the context of nonparametric linkage analysis. The objective is to estimate genome-wide p-values, i.e. the probability that the maximal linkage score exceeds given thresholds under the null hypothesis of no linkage. In order to reduce variance of the estimate for large thresholds, we simulate linkage scores under a distribution different from the null with an artificial disease locus positioned somewhere along the genome. To compensate for the fact that we simulate under the wrong distribution, the simulated scores are reweighted using a certain likelihood ratio. If the sampling distribution are properly chosen the variance of the corresponding estimate is reduced. This results in accurate genome-wide p-value estimates for a wide range of large thresholds with a substantially smaller cost adjusted relative efficiency with respect to standard unweighted simulation.We illustrate the performance of the method for several pedigree examples, discuss implementation including the amount of variance reduction and describe some possible generalizations.