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Mormino EC, Sperling RA, Holmes AJ, Buckner RL, De Jager PL, Smoller JW, Sabuncu MR, Alzheimer's Disease Neuroimaging Initiative. Polygenic risk of Alzheimer disease is associated with early- and late-life processes. Neurology. 2016 Aug 2;87(5):481-8. Epub 2016 Jul 6 PubMed.
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This is a very interesting paper indeed. It shows, perhaps not surprisingly, that genetic risk loci for AD also predict endophenotypes associated with AD, such as memory loss, lower executive functioning, reduced hippocampal volume, etc., in younger, so far unaffected subjects. More interestingly, it shows how much stronger the associations are if you calculate a polygenic risk score (PGRS) including loci below the threshold of formal genome wide significance of 5 x 10-8 commonly accepted in genome-wide association studies (GWAS), implying that there are many more loci yet to be found influencing AD risk and associated phenotypes. Some people in the research community are saying, “That’s enough GWAS; we already have 19 significant loci and those are the biggest ones.” But the lesson of this paper is that even larger sample sizes will find new loci that may lead us to new pathways and new biology. This is certainly the experience with the recent success of GWAS for schizophrenia, where 108 separate loci now have been identified, leading us to previously unsuspected biology and strong leads for new therapies. And it is important to remember that there is no connection between the effect size of a risk locus and its importance as a potential drug target, for example, the extremely successful cholesterol-lowering statin drugs target HMGCR, a rather small GWAS hit for circulating lipid levels.
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