New Paper on Genetic Influence

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Julie G
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New Paper on Genetic Influence

Postby Julie G » Mon Mar 30, 2015 5:19 pm

This looks like a potentially important paper on the genetic contributors to AD. I haven't read it yet, but both APOE ε4 and the HME genes seem to be the biggest culprits.

Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer’s disease ... 0304-6.pdf

Heritability of Alzheimer‘s disease (AD) is estimated at 74% and genetic contributors have been widely sought. The ε4 allele of apolipoprotein E (APOE) remains the strongest common risk factor for AD, with numerous other common variants contributing only modest risk for disease. Variability in clinical presentation of AD, which is typically amnestic (AmnAD) but can less commonly involve visuospatial, language and/or dysexecutive syndromes (atypical or AtAD), further complicates genetic analyses. Taking a multi-locus approach may increase the ability to identify individuals at highest risk for any AD syndrome. In this study, we sought to develop and investigate the utility of a multi-variant genetic risk assessment on a cohort of phenotypically heterogeneous patients with sporadic AD clinical diagnoses.

We confirmed APOE ε4 as a strong risk factor for AD. A 17-marker risk panel predicted AD significantly better than APOE genotype alone (P < 0.00001) in the Discovery cohort, but not in the Validation cohort. In decision tree analyses, we found that APOE best differentiated cases from controls only in AmnAD but not AtAD. In AtAD, HFE SNP rs1799945 was the strongest predictor of disease; variation in HFE has previously been implicated in AD risk in non-ε4 carriers.

Our study suggests that APOE ε4 remains the best predictor of broad AD risk when compared to multiple other genetic factors with modest effects, that phenotypic heterogeneity in broad AD can complicate simple polygenic risk modeling, and supports the association between HFE and AD risk in individuals without APOE ε4.

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Re: New Paper on Genetic Influence

Postby J11 » Mon Mar 30, 2015 6:47 pm

You really have to applaud the authors for trying to think outside the APOE box.

There must be a fair number of people out there who are also stuck in the non APOE 4 familial dominant AD trap and this article points in the direction of actually considering these families. The problem in the article was they did not appear to separate the sporadic and dominant non APOE 4s. Further, in their study some of the sub-groups only had about 10 non APOE 4s. APOE 4s will always be easier to deal with because they are more homogenous and are more likely to have AD. Non APOE 4s can be more diverse. This might be why there seems to be only a few studies that consider the non 4s. Analyzing the IGAP study by APOE 4 genotype might help uncover the AD risk architecture for those lacking epsilon 4.

Yet, it is very unclear how the authors could have believed that their small sample of people could yield new results. It is hard to imagine that the new SNPs listed in Table 2 could possibly replicate in a larger sample. The IGAP study involved 75,000 people. Such a large sample severely restricts the outstanding AD risk variants above 5% MAF. For example, the probability of finding AD SNPs with population frequency greater than 25% and OR much more than 1.1 is likely now to be quite low. In fact, IGAP did not find any such variants. The article claimed that rs1799945 had a population frequency of 15% and OR=2.83 on the basis of a discovery cohort of 200. alzgene has over 4000 people genotyped at this SNP with OR=0.90 and they were unable to determine whether or not this SNP has an OR different from 1. With large scale GWAS in many illnesses, any claims of large effect with a frequency above a few percent in any major disease should now invite intense scrutiny.

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