Assessing the Contribution Family Data Can Make to Case‐Control Studies of Rare Variants

Centre for Psychiatry, Barts and The London School of Medicine and Dentistry, London, UK.
Annals of Human Genetics (Impact Factor: 2.21). 06/2011; 75(5):630-8. DOI: 10.1111/j.1469-1809.2011.00660.x
Source: PubMed


When pathogenic variants are rare then even among cases the proportion of subjects possessing a variant might be low, meaning that very large samples might be required to conclusively demonstrate evidence of an effect. Relatives of subjects within a case-control sample might provide useful additional information.
The method of model-free linkage analysis implemented in MFLINK was adapted to incorporate linkage disequilibrium (LD) parameters in order to test for an effect of a putative pathogenic variant in complete LD with a disease locus. The effect of adding in to the analysis relatives of cases and controls found to carry the variant was investigated.
When affected siblings or cousins of cases possessing the variant were incorporated they had a large effect on the results obtained. The evidence for involvement increased or reduced as expected, depending on whether or not the relatives themselves were found to possess the variant. The size of the effect was large relative to that expected from just increasing the size of a standard case-control sample.
Affected relatives offer a valuable resource to assist the interpretation of case-control studies of rare variants. The method is capable of including other relative types and can deal with complex pedigrees.

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Available from: David Curtis, Jun 16, 2015
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    • "The reason for using these two cohorts, rather than other subjects included in UK10K, was primarily that they represented two groups, each of which was phenotypically fairly homogeneous and which had similar geographical origins. The "case–case" design for association studies has the advantage that one does not require an additional set of controls but may have the disadvantage that if allele frequencies differ between the groups then one may not know which is the relevant phenotype (Curtis et al., 2011). As described elsewhere (The UK10K Consortium, 2015), the exome was targeted with the Agilent SureSelect 50Mb V3 exome library, followed by Illumina next generation sequencing with 75bp paired-end reads. "
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