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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.

SUBMITTER: Jain N

PROVIDER: S-EPMC6028053 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Genetic Modifiers in Neurodegeneration.

Jain Nimansha N Chen-Plotkin Alice S AS

Current genetic medicine reports 20180205 1

<h4>Purpose of review</h4>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).<h4>Recent findings</h4>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 t ...[more]

PMID: 29977663

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Project description:Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene in both humans and the orthologous PCK rat model. Although ARPKD results solely from PKHD1 mutations, the disease onset and severity are highly variable, indicating that other unknown genetic risk factor(s) modify ARPKD-associated phenotypes. To identify genetic modifiers of ARPKD severity, we created two genetically distinct Pkhd1 congenic rat strains on the Fawn-Hooded Hypertensive (FHH) and the Dahl S (SS) rat backgrounds (denoted FHH.Pkhd1 and SS.Pkhd1, respectively) that harbor the PCK-derived Pkhd1 allele. The FHH.Pkhd1 and SS.Pkhd1 strains had lower renal cyst formation at 30 days-of-age (5±2% and 8±2% cystic, respectively; P<0.001) compared to the PCK kidneys (26±4% cystic), which coincided with significantly reduced kidney weights in the FHH.Pkhd1 and SS.Pkhd1. Liver cyst formation and liver weight did not differ between PCK, FHH.Pkhd1, and SS.Pkhd1. These data indicated that the PCK genome harbors genetic modifier(s) of ARPKD severity that are not present in the FHH and SS genomes. Using high density SNP array genotyping and microarray expression analysis, we identified 50 potential modifiers of ARPKD severity in the PCK rat. Of these candidates, a damaging nonsynonymous variant in Nphp4 stood out as the most likely candidate based on variant segregation, protein modeling, network analysis, and gene ontology. Nphp4 is widely associated with the autosomal recessive cilliopathy and nephronopthisis, but had not been previously implicated in the molecular or cellular pathophysiology of ARPKD. Collectively, these data provide genetic evidence of disease modifier(s) in the PCK model of ARPKD and prioritized multiple candidates, including NPHP4, for further investigation in ARPKD pathogenesis. In this study, we used microarray to analyze transcript expression in the kidneys of 30 day old SD (n=4), PCK (n=4), FHH (n=4), FHH.Pkhd1 (n=4), SS (n=4), and SS.Pkhd1 (n=4). Samples were pooled and the pooled samples were run in triplicate. The 30 day timepoint was chosen because the differences in renal cyst formation between PCK, FHH.Pkhd1, and SS.Pkhd1 were greatest at this timepoint. To account for genetic strain differences that do not contribute to ARPKD severity, gene expression of each cystic rat strain was compared to its parental strain.

Dataset Information

Genetic Modifiers in Neurodegeneration.

Publications

Genetic Modifiers in Neurodegeneration.

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