Allele‐Sharing Statistics Using Information on Family History

When conducting genetic studies for complex traits, large samples are commonly required to detect new genetic factors. A possible strategy to decrease the sample size is to reduce heterogeneity using available information. In this paper we propose a new class of model‐free linkage analysis statistics which takes into account the information given by the ungenotyped affected relatives (positive family history). This information is included into the scoring function of classical allele‐sharing statistics. We studied pedigrees of affected sibling pairs with one ungenotyped affected relative. We show that, for rare allele common complex diseases, the proposed method increases the expected power to detect linkage. Allele‐sharing methods were applied to the symptomatic osteoarthritis GARP study where taking into account the family‐history increased considerably the evidence of linkage in the region of the DIO2 susceptibility locus.     

Variation of Estimates of SNP and Haplotype Diversity and Linkage Disequilibrium in Samples from the Same Population Due to Experimental and Evolutionary Sample Size

Studies of genetic polymorphisms and diversity between and within human populations are increasingly characterised by a very large number of genetic markers but using a relatively small number of individuals from which DNA samples were taken. In this report we examine the limitations of a small experimental sample size relative to a large genomic sample size, and quantify the sampling variance of a number of measures of diversity and linkage disequilibrium. The relationship between sample size and observed levels of polymorphism and haplotype diversity at the level of a gene is investigated under a neutral model of sequence evolution, using coalescent simulations. It is shown that the effect of evolutionary sampling, as manifested by differences between samples (genes) in measures of diversity estimated using very large sample sizes, is substantial, with a coefficient of variation of the number of detected polymorphic SNPs or haplotypes in the order of 15%. The effect of experimental design (sample size) is also very large, and a number of 'significant' results reported in the literature can be explained by sampling alone. The expected correlation coefficient of measures of linkage disequilibrium across samples from the same population has been quantified and found to be consistent with empirical estimates from the literature.     

High-Resolution Characterization of Linkage Disequilibrium Structure and Selection of Tagging Single Nucleotide Polymorphisms: Application to the Cholesteryl Ester Transfer Protein Gene

Full characterization of intragenic variation may improve candidate gene associations. This study selected tagging (t) single nucleotide polymorphisms (SNPs) to comprehensively represent genetic variability in the cholesteryl ester transfer protein ( CETP ) gene. Nineteen SNPs were identified in 50 unrelated individuals in the SNP discovery phase, and 13 intronic SNPs were added from the literature. These 32 SNPs were genotyped in 339 apparently healthy individuals and 190 coronary artery disease (CAD) patients. Using phased haplotypes, linkage disequilibrium (LD) structure was characterized and tSNPs selected using a principal component analysis (PCA) method. In healthy individuals, seven LD groups were identified that accounted for 93.4% of the observed genetic variation. These LD groups highlighted a complex LD structure for CETP , including both recombination and mutation, and eleven tSNPs were selected. Among CAD patients the results were essentially the same. Results from PCA using diploid genotype data were reasonably comparable. Finally, the selected tSNPs successfully represented the association evidence discovered for all of the other SNPs studied. This study provides an optimal set of tSNPs for association analyses of CETP . The observed complexity of LD structure highlights the importance of using methods, such as PCA, that allow for multiple dynamics in intragenic LD structure.     

Combined Linkage and Association Analyses of the 124-bp Allele of Marker D2S2944 with Anxiety, Depression, Neuroticism and Major Depression

A central issue in psychiatric genetics is whether positive findings replicate. Zubenko et al. (2002b, Mol. Psychiatry 7:460–467) reported an association of the 124-bp allele of D2S2944 with recurrent early-onset major depression for females. We tested for association of this allele to continuous measures of anxiety, depression and neuroticism in a Dutch sample of 347 males and 448 females, and to DSM-IV major depression in a subsample of 210 males and 295 females. The association of the 124-bp allele to depression in females was not replicated, but there were significant associations (not significant after correction for multiple testing) with anxiety and anxious depression in males. However, the association occurred in the absence of evidence for linkage in this region on chromosome 2.