Genetic Modifiers in Neurodegeneration

Abstract

Purpose of review: To review the evidence for genetic modifier effects in the neurodegenerative diseases Huntington's Disease (HD), Frontotemporal Lobar Degeneration (FTLD), Alzheimer's Disease (AD), and Parkinson's Disease (PD).

Recent findings: Increasingly, we understand human disease genetics less through the lens of single-locus/single-trait effects, and more through that of polygenic contributions to disease risk. In addition, specific examples of genetic modifier effects of the chromosome 7 gene TMEM106B on various target genes including those causal for Mendelian classes of FTLD - GRN and c9orf72 - have emerged from both genetic cohort studies and mechanistic examinations of biological pathways.

Summary: Here, we summarize the literature reporting genetic modifier effects in HD, FTLD, AD, and PD. We further contextualize reported genetic modifier effects in these diseases in terms of insight they may lend to the concept of a polygenic landscape for the major neurodegenerative diseases.

Keywords: APOE; Alzheimer’s Disease; FTLD; Genetic modifier; Parkinson’s Disease; TMEM106B; neurodegeneration.

Figure 1

A. Representation of types of genetic variants and effects on trait, with variant frequency on the X-axis and effect size on the Y-axis. Genetic modifier effects are represented by arrows emanating from target gene (blue dot) loci. B. Known genetic modifier effects in AD, PD, and FTLD. Target gene names are shown in red, and modifier loci names are shown in black, with direction of effect indicated by arrow. AD loci are highlighted by the pink oval, FTLD loci by the green oval, and PD loci by the tan oval. Arrows are not drawn to scale, and some genetic modifier loci are unknown (question marks).