GenoRisk: A polygenic risk score for Alzheimer's disease Dickson, Samuel P.; Hendrix, Suzanne B.; Brown, Bruce L. ...
Alzheimer's & dementia : translational research & clinical interventions,
2021, Letnik:
7, Številka:
1
Journal Article
Recenzirano
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Introduction
Recent clinical trials are considering inclusion of more than just apolipoprotein E (APOE) ε4 genotype as a way of reducing variability in analysis of outcomes.
Methods
Case‐control data ...were used to compare the capacity of age, sex, and 58 Alzheimer's disease (AD)–associated single nucleotide polymorphisms (SNPs) to predict AD status using several statistical models. Model performance was assessed with Brier scores and tenfold cross‐validation. Genotype and sex × age estimates from the best performing model were combined with age and intercept estimates from the general population to develop a personalized genetic risk score, termed age, and sex‐adjusted GenoRisk.
Results
The elastic net model that included age, age x sex interaction, allelic APOE terms, and 29 additional SNPs performed the best. This model explained an additional 19% of the heritable risk compared to APOE genotype alone and achieved an area under the curve of 0.747.
Discussion
GenoRisk could improve the risk assessment of individuals identified for prevention studies.
Alzheimer’s disease affects millions of people worldwide and incidence is expected to rise as the population ages, but no effective therapies exist despite decades of research and more than 20 known ...disease markers. Research has shown that Alzheimer’s disease’s missing heritability remains extensive with an estimated 25% of phenotypic variance unexplained by known variants. The missing heritability may be explained by missing variants or by epistasis. Researchers often focus on individual loci rather than epistatic interactions, which is likely an oversimplification of the underlying biology since most phenotypes are affected by multiple genes. Focusing research efforts on epistasis will be critical to resolving Alzheimer’s disease etiology, and a major key to identifying and properly interpreting key epistatic interactions will be bridging the gap between statistical and biological epistasis. This review covers the current state of epistasis research in Alzheimer’s disease and how researchers can bridge the gap between statistical and biological epistasis to help resolve Alzheimer’s disease etiology.
The mitochondria are essential organelles and are the location of cellular respiration, which is responsible for the majority of ATP production. Each cell contains multiple mitochondria, and each ...mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. The regulation of mitochondrial copy number by nuclear genes has been studied extensively. While mitochondrial variation has been associated with longevity and some of the diseases known to have reduced mitochondrial copy number, the role that the mitochondrial genome itself has in regulating mitochondrial copy number remains poorly understood.
We analyzed the complete mitochondrial genomes from 1007 individuals randomly selected from the Cache County Study on Memory Health and Aging utilizing the inferred evolutionary history of the mitochondrial haplotypes present in our dataset to identify sequence variation and mitochondrial haplotypes associated with changes in mitochondrial copy number. Three variants belonging to mitochondrial haplogroups U5A1 and T2 were significantly associated with higher mitochondrial copy number in our dataset.
We identified three variants associated with higher mitochondrial copy number and suggest several hypotheses for how these variants influence mitochondrial copy number by interacting with known regulators of mitochondrial copy number. Our results are the first to report sequence variation in the mitochondrial genome that causes changes in mitochondrial copy number. The identification of these variants that increase mtDNA copy number has important implications in understanding the pathological processes that underlie these phenotypes.
Abstract
Ramp sequences occur when the average translational efficiency of codons near the 5′ end of highly expressed genes is significantly lower than the rest of the gene sequence, which ...counterintuitively increases translational efficiency by decreasing downstream ribosomal collisions. Here, we show that the relative codon adaptiveness within different tissues changes the existence of a ramp sequence without altering the underlying genetic code. We present the first comprehensive analysis of tissue and cell type-specific ramp sequences and report 3108 genes with ramp sequences that change between tissues and cell types, which corresponds with increased gene expression within those tissues and cells. The Ramp Atlas (https://ramps.byu.edu/) allows researchers to query precomputed ramp sequences in 18 388 genes across 62 tissues and 66 cell types and calculate tissue-specific ramp sequences from user-uploaded FASTA files through an intuitive web interface. We used The Ramp Atlas to identify seven SARS-CoV-2 genes and seven human SARS-CoV-2 entry factor genes with tissue-specific ramp sequences that may help explain viral proliferation within those tissues. We anticipate that The Ramp Atlas will facilitate personalized and creative tissue-specific ramp sequence analyses for both human and viral genes that will increase our ability to utilize this often-overlooked regulatory region.
The original version of this article 1 unfortunately contained a typographical error. The 'Alzheimer's Disease Neuroimaging Initiative' was erroneously included as 'Alzheimer's Disease Neuroimaging ...Initative' in the author list of the article.
Aortopathies are a group of disorders characterized by aneurysms, dilation, and tortuosity of the aorta. Because of the phenotypic overlap and genetic heterogeneity of diseases featuring aortopathy, ...molecular testing is often required for timely and correct diagnosis of affected individuals. In this setting next generation sequencing (NGS) offers several advantages over traditional molecular techniques.
The purpose of our study was to compare NGS enrichment methods for a clinical assay targeting the nine genes known to be associated with aortopathy. RainDance emulsion PCR and SureSelect RNA-bait hybridization capture enrichment methods were directly compared by enriching DNA from eight samples. Enriched samples were barcoded, pooled, and sequenced on the Illumina HiSeq2000 platform. Depth of coverage, consistency of coverage across samples, and the overlap of variants identified were assessed. This data was also compared to whole-exome sequencing data from ten individuals.
Read depth was greater and less variable among samples that had been enriched using the RNA-bait hybridization capture enrichment method. In addition, samples enriched by hybridization capture had fewer exons with mean coverage less than 10, reducing the need for followup Sanger sequencing. Variants sets produced were 77% concordant, with both techniques yielding similar numbers of discordant variants.
When comparing the design flexibility, performance, and cost of the targeted enrichment methods to whole-exome sequencing, the RNA-bait hybridization capture enrichment gene panel offers the better solution for interrogating the aortopathy genes in a clinical laboratory setting.
Abstract Introduction Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 ( CLU - MS4A4E ) and rs3865444-rs670139 ( CD33 - MS4A4E ). We evaluate these interactions in the ...largest data set for an epistasis study. Methods We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E ( APOE ) ε4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants. Results Results support the CLU - MS4A4E interaction and a dominant effect. An association between CLU - MS4A4E and APOE ε4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45, and 8.0, respectively. We identified potential causal variants. Discussion We replicated the CLU - MS4A4E interaction in a large case-control series and observed APOE ε4 and possible dominant effect. The CLU - MS4A4E OR is higher than any Alzheimer's disease locus except APOE ε4, APP , and TREM2 . We estimated an 8% decrease in Alzheimer's disease incidence without CLU - MS4A4E risk alleles and identified potential causal variants.
Population stratification is a key concern for genetic association analyses. In addition, extreme homogeneity of ethnic origins of a population can make it difficult to interpret how genetic ...associations in that population may translate into other populations. Here we have evaluated the genetic substructure of samples from the Cache County study relative to the HapMap Reference populations and data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
Our findings show that the Cache County study is similar in ethnic diversity to the self-reported "Whites" in the ADNI sample and less homogenous than the HapMap CEU population.
We conclude that the Cache County study is genetically representative of the general European American population in the USA and is an appropriate population for conducting broadly applicable genetic studies.
Polygenic scores (or genetic risk scores) quantify the aggregate of small effects from many common genetic loci that have been associated with a trait through genome-wide association. Polygenic ...scores were first used successfully in schizophrenia and have since been applied to multiple phenotypes including multiple sclerosis, rheumatoid arthritis, and height. Because human height is an easily-measured and complex polygenic trait, polygenic height scores provide exciting insights into the predictability of aggregate common variant effect on the phenotype. Shawn Bradley is an extremely tall former professional basketball player from Brigham Young University and the National Basketball Association (NBA), measuring 2.29 meters (7′6″, 99.99999th percentile for height) tall, with no known medical conditions. Here, we present a case where a rare combination of common SNPs in one individual results in an extremely high polygenic height score that is correlated with an extreme phenotype. While polygenic scores are not clinically significant in the average case, our findings suggest that for extreme phenotypes, polygenic scores may be more successful for the prediction of individuals.
Since the advent of next-generation sequencing many previously untestable hypotheses have been realized. Next-generation sequencing has been used for a wide range of studies in diverse fields such as ...population and medical genetics, phylogenetics, microbiology, and others. However, this novel technology has created unanticipated challenges such as the large numbers of genetic variants. Each caucasian genome has more than four million single nucleotide variants, insertions and deletions, copy number variants, and structural variants. Several formats have been suggested for storing these variants; however, the variant call format (VCF) has become the community standard.
We developed new software called the Variant Tool Chest (VTC) to provide much needed tools to work with VCF files. VTC provides a variety of tools for manipulating, comparing, and analyzing VCF files beyond the functionality of existing tools. In addition, VTC was written to be easily extended with new tools.
Variant Tool Chest brings new and important functionality that complements and integrates well with existing software. VTC is available at https://github.com/mebbert/VariantToolChest.
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