Developing improved methods to analyse next generation sequence data

The objectives are to identify and characterise genes and genetic variants which increase or decrease the risk of developing Alzheimer's disease.
Exome sequenced and whole genome sequenced cases and controls will be analysed. The predicted function of DNA variants will be obtained using
software such as VEP, PolyPhen, SIFT. Weighted burden analysis will be performed wherein variants are given higher weights if they are predicted to
have a major effect on protein function and/or if they are rare. For each gene, in each subject the weights for the DNA variants possessed by that
subject will be summed to produce a score. The scores between cases and controls will be compared using logistic regression and incorporating
relevant covariates such as sex, age, principal components. If scores are on average higher in cases this indicates that damage to the gene
increases risk of Alzheimer's disease. If scores are higher in controls this indicates that damage to the gene reduces risk. Sets of genes will also be
analysed in a similar way. The method has been applied to a smaller ADSP dataset:

Curtis D, Bakaya K, Sharma L, Bandyopadhyay S. Weighted burden analysis of exome-sequenced late onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways. Ann Hum Genet 2020
https://doi.org/10.1111/ahg.12375

We will analyse whether variants in DNA can interfere with the functioning of particular genes and either increase or decrease the risk of developing
Alzheimer's disease. We will examine all the variants in a gene observed in large samples of people with and without Alzheimer's disease to see if
variants are more commonly seen in one or other group. We will weight the variants to that more attention is paid to those which are rare and those
which are predicted to have a major effect on the functioning of the gene. If we see more variants in the people with Alzheimer's disease then this
suggests that damaging that gene could increase risk of illness. If the people without disease have more variants in a gene then that could suggest
that damaging that gene would actually protect against Alzheimer's disease. Understanding these effects will ultimately assist in the development of
methods to treat or prevent the disease.