The Fox and the Rabbits—Environmental Variables and Population Genetics (1) Replication Problems in Association Studies and the Untapped Power of GWAS (2) Vitamin A Deficiency, Herpes Simplex Reactivation and Other Causes of Alzheimer's Disease
Classical population genetics shows that varying permutations of genes and risk factors permit or disallow the effects of causative agents, depending on circumstance. For example, genes and environment determine whether a fox kills black or white rabbits on snow or black ash covered islands. Risk promoting effects are different on each island, but obscured by meta-analysis or GWAS data from both islands, unless partitioned by different contributory factors. In Alzheimer's disease, the foxes appear to be herpes, borrelia or chlamydial infection, hypercholesterolemia, hyperhomocysteinaemia, diabetes, cerebral hypoperfusion, oestrogen depletion, or vitamin A deficiency, all of which promote beta-amyloid deposition in animal models—without the aid of gene variants. All relate to risk factors and subsets of susceptibility genes, which condition their effects. All are less prevalent in convents, where nuns appear less susceptible to the ravages of ageing. Antagonism of the antimicrobial properties of beta-amyloid by Abeta autoantibodies in the ageing population, likely generated by antibodies raised to beta-amyloid/pathogen protein homologues, may play a role in this scenario. These agents are treatable by diet and drugs, vitamin supplementation, pathogen detection and elimination, and autoantibody removal, although again, the beneficial effects of individual treatments may be tempered by genes and environment. 1. Introduction If there is one factor common to complex polygenic diseases it is the heterogeneity in both gene and risk factor association studies. Although these have discovered key genes and risk factors, the results for most are invariably confounded by conflicting data [1]. In the genetic arena, the clear familial component of many diseases has driven the search for major genes using genome-wide association studies (GWAS) with large numbers of patients pooled from different regions [2]. Such studies have been able to discover rare variants that play a major role in a small percentage of patients, for example VIPR2 in schizophrenia [3]. However, in complex diseases, these have failed to find major genes relevant to all patients [4], instead unearthing yet more genes of small effect, whose risk promoting effects are yet again contested, as is the case with CR1 and PICALM, which have not been confirmed as risk factors for Alzheimer’s disease in Chinese patients [5] despite extensive evidence in Caucasian studies [6]. GWAS studies have, however, been more successful in uncovering larger numbers of genes of greater effect for simpler traits such as
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