In a report published in the American Journal of Human Genetics, Shulman and collaborators report a two-stage strategy to characterize new genetic determinants of Alzheimer’s disease. They first performed a genomewide association study (GWAS) in an autopsy cohort including 227 participants (91 AD cases, 50 MCI cases, and 86 controls). They selected their best hits for further analyses (p value less than 10^-3).

At this stage, they coupled this association study with a functional screening, with the postulate that convergence of both association and functional data might allow to restrict false-positive results, the main problem inherent to the genetic analyses, and to finally pick up relevant genes in the AD process.

To perform this functional screening, they used a Drosophila model on the basis of in vivo interactions with the neurotoxicity of tau. They reported that SLC2A14 is a promising gene of interest, associated with AD risk. The Drosophila ortholog was associated with tau toxicity.

The number of cases and controls analyzed in the GWAS...  Read more

In a report published in the American Journal of Human Genetics, Shulman and collaborators report a two-stage strategy to characterize new genetic determinants of Alzheimer’s disease. They first performed a genomewide association study (GWAS) in an autopsy cohort including 227 participants (91 AD cases, 50 MCI cases, and 86 controls). They selected their best hits for further analyses (p value less than 10^-3).

At this stage, they coupled this association study with a functional screening, with the postulate that convergence of both association and functional data might allow to restrict false-positive results, the main problem inherent to the genetic analyses, and to finally pick up relevant genes in the AD process.

To perform this functional screening, they used a Drosophila model on the basis of in vivo interactions with the neurotoxicity of tau. They reported that SLC2A14 is a promising gene of interest, associated with AD risk. The Drosophila ortholog was associated with tau toxicity.

The number of cases and controls analyzed in the GWAS step is limited, and replication/validation works are clearly needed. Unfortunately, this SNP was not associated with AD risk in our French GWAS (p = 0.76). However, the design of the two-stage strategy is clever and appears to be very powerful. The main advantages are as follows:

• Most fundamental neuronal cell biological processes, such as synapse formation, neuronal communication, membrane trafficking, cell cycle regulation, and cell death, are very similar in Drosophila to those seen in humans. Hence, human neurodegenerative proteinopathy-mediated neurotoxicity can be successfully modeled in flies.
• The high breeding rate and ease of handling and maintenance enables systematic functional genomic screening at a scale which is not conceivable in rodents. GWAS often define loci of interest encompassing several genes, and it can be difficult to determine which one is causal using only both genetic and literature bases. The systematic screening of all the genes within a locus can thus be a good option to finally pick up the relevant one.
• Because GWAS are without hypothesis-driven strategies, an easy in vivo screening could provide a first attempt to understand how the genes are involved in the AD process.
• To screen for genes exhibiting only suggestive associations can possibly highlight potential genetic determinants which would have been rejected only on statistical grounds (false negative).

However, it is worth noting that this strategy also presents important limitations to keep in mind:

• As mentioned by the authors, they only used a tau toxicity model and, of course, it is possible that the GWAS-defined genes are simply not involved in such a mechanism. Other complementary relevant Drosophila models might be of particular interest, e.g., Aβ toxicity models. As a consequence, it is not possible to determine whether a gene associated with AD risk is a false positive or not on the basis of this in vivo screening.
• Even if 75 percent of the genes involved in human genetic disorders have at least one fly homologue (despite the considerable evolutionary distance between flies and humans), Drosophila could not allow for screening of all the GWAS-defined genes. For instance, no fly homologues have been reported for CLU and CR1, whereas clear homologues exist for BIN1 and PICALM.

In conclusion, we think that this two-stage strategy will be particularly relevant when associated with a powerful GWAS. In this context, the recent announcement of the I-GAP consortium opens new perspectives with the possibility to screen for dozen of GWAS-defined genes/loci showing association reaching genomewide significant or suggestive p values.

View all comments by Bart Dermaut
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