. PLD3 gene and processing of APP. Nature. 2017 Jan 25;541(7638):E1-E2. PubMed.


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  1. This paper from the De Strooper lab convincingly shows that there is not a clear effect of PLD3 on APP biology and reignites the debate on whether PLD3 is an AD gene (Cruchaga et al., 2013).

    Genetic analysis looking for rare variants is subject to difficult confounds. Usually, cases and controls are collected in subtly different ways and they may not be perfectly matched.  In the U.K., for example, a higher proportion of controls were collected from the Cambridge area. These subtle population differences don’t cause a problem in GWAs with genes with modest effect sizes, but as studies look for GWAs hits of very small effect sizes or at rare variants like PLD3, these small population stratification issues can cause problems. For example, a founder variant in the Cambridge area could be mistaken for a protective allele in this sample. In the case of PLD3, replication attempts have given mixed results with no clear outcome (van der Lee et al., 2015; Lambert et al., 2015Heilmann et al., 2015Hooli et al., 2015). One hopes that a clear outcome on PLD3 will come from the massive sequencing efforts both in the U.S. and in Europe. PLD3 is not alone in remaining in pathogenic limbo. Since TREM2 was reported, no other new genes have yet been consistently replicated. In contrast, rare variants found in GWAs hits seem to give more consistent results.

    Replication of genetic associations, outside of the first study, remains the most effective mechanism for deciding what is correct.


    . Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature. 2014 Jan 23;505(7484):550-4. Epub 2013 Dec 11 PubMed.

    . PLD3 variants in population studies. Nature. 2015 Apr 2;520(7545):E2-3. PubMed.

    . PLD3 and sporadic Alzheimer's disease risk. Nature. 2015 Apr 2;520(7545):E1. PubMed.

    . PLD3 in non-familial Alzheimer's disease. Nature. 2015 Apr 2;520(7545):E3-5. PubMed.

    . PLD3 gene variants and Alzheimer's disease. Nature. 2015 Apr 2;520(7545):E7-8. PubMed.

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  1. With PLD3, Forget APP...Think Lysosome Instead