. The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data. Am J Hum Genet. 2017 Feb 2;100(2):193-204. Epub 2017 Jan 5 PubMed.


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  1. I think it’s great to have new methods to assess rare variability in cohorts of families. Different methods have different limitations so it’s good to see novel, apparently robust approaches to use family based whole-exome and whole-genome sequencing data to look for associations between rare variants and complex diseases.

    I would say that one highlight of this paper is that the authors used their method to analyze a large whole-genome sequenced cohort of AD families (particularly when these are the first results from the ADSP sequencing project to be published, I believe).

    The findings are very interesting, although I didn’t manage to find a way to determine which family members have which variants and consequently can’t figure out if the numbers of alternative alleles for one variant in one gene are all found in the same family or in different families (the latter would make a much stronger case for the involvement of the variant/gene in AD, but I suspect the former is more likely).

    Of course it will be essential to have replication of these findings. The authors seem to associate true/false positivity of the findings with previous associations of the candidate genes with AD and with previous functional studies of the proteins, which could be misleading. They mention the extension and follow-up phases for this ADSP project and the sharing of WES data by individual investigators as important steps for future replication studies. I wonder if, already at this stage, they did any kind of analysis to the accompanying ADSP WES data from 5,000 sporadic cases and 5,000 controls—although not the same study design, it would be interesting to know if there is any hint of association there.


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