Genomic Markers for Essential Tremor

There are many reports suggesting an important role of genetic factors in the etiopathogenesis of essential tremor (ET), encouraging continuing the research for possible genetic markers. Linkage studies in families with ET have identified 4 genes/loci for familial ET, although the responsible gene(s) have not been identified. Genome-wide association studies (GWAS) described several variants in LINGO1, SLC1A2, STK32B, PPARGC1A, and CTNNA3, related with ET, but none of them have been confirmed in replication studies. In addition, the case-control association studies performed for candidate variants have not convincingly linked any gene with the risk for ET. Exome studies described the association of several genes with familial ET (FUS, HTRA2, TENM4, SORT1, SCN11A, NOTCH2NLC, NOS3, KCNS2, HAPLN4, USP46, CACNA1G, SLIT3, CCDC183, MMP10, and GPR151), but they were found only in singular families and, again, not found in other families or other populations, suggesting that some can be private polymorphisms. The search for responsible genes for ET is still ongoing.

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Genetic Determinants of Paget’s Disease of Bone

Current Osteoporosis Reports ◽

10.1007/s11914-021-00676-w ◽

2021 ◽

Author(s):

Navnit S. Makaram ◽

Stuart H. Ralston

Keyword(s):

Genetic Factors ◽

Association Studies ◽

Paget’S Disease ◽

Paget's Disease ◽

Paget’S Disease Of Bone ◽

Genome Wide Association Studies ◽

Paget's Disease Of Bone ◽

Genome Wide ◽

Family Based

Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

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Genetic and microbiome influence on lipid metabolism and dyslipidemia

Physiological Genomics ◽

10.1152/physiolgenomics.00053.2017 ◽

2018 ◽

Vol 50 (2) ◽

pp. 117-126 ◽

Cited By ~ 26

Author(s):

Maria Luisa Matey-Hernandez ◽

Frances M. K. Williams ◽

Tilly Potter ◽

Ana M. Valdes ◽

Tim D. Spector ◽

...

Keyword(s):

Lipid Metabolism ◽

Gut Microbiome ◽

Genetic Factors ◽

Association Studies ◽

Interindividual Variation ◽

Genome Wide Association Studies ◽

Therapeutic Implications ◽

Genome Wide ◽

Dietary Components

Disruption in the metabolism of lipids is broadly classified under dyslipidemia and relates to the concentration of lipids in the blood. Dyslipidemia is a predictor of cardio-metabolic disease including obesity. Traditionally, the large interindividual variation has been related to genetic factors and diet. Genome-wide association studies have identified over 150 loci related to abnormal lipid levels, explaining ~40% of the total variation. Part of the unexplained variance has been attributed to environmental factors including diet, but the extent of the dietary contribution remains unquantified. Furthermore, other factors are likely to influence lipid metabolism including the gut microbiome, which plays an important role in the digestion of different dietary components including fats and polysaccharides. Here we describe the contributing role of host genetics and the gut microbiome to dyslipidemia and discuss the potential therapeutic implications of advances in understanding the gut microbiome to the treatment of dyslipidemia.

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The current review of adolescent obesity: the role of genetic factors

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0480 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Birsen Yılmaz ◽

Makbule Gezmen Karadağ

Keyword(s):

Genetic Factors ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Heterogeneous Condition ◽

Current Review ◽

Genome Wide

AbstractObesity, a complex, multi-factor and heterogeneous condition, is thought to result from the interaction of environmental and genetic factors. Considering the result of adolescence obesity in adulthood, the role of genetic factors comes to the fore. Recently, many genome-wide association studies (GWAS) have been conducted and many loci associated with adiposity have been identified. In adolescents, the strongest association with obesity has been found in single nucleotide polymorphisms (SNP) in the FTO gene. Besides FTO, GWAS showed consistent effects between variants in MC4R, TMEM18, TNNI3K, SEC16B, GNPDA2, POMC and obesity. However, these variants may not have similar effects for all ethnic groups. Although recently genetic factors are considered to contribute to obesity, relatively little is known about the specific loci related to obesity and the mechanisms by which they cause obesity.

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Stroke Genetics: Turning Discoveries into Clinical Applications

Stroke ◽

10.1161/strokeaha.121.032616 ◽

2021 ◽

Author(s):

Martin Dichgans ◽

Nathalie Beaufort ◽

Stephanie Debette ◽

Christopher D. Anderson

Keyword(s):

Mendelian Randomization ◽

Association Studies ◽

Clinical Applications ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Neuroprotective Agents ◽

Experimental Systems ◽

Genome Wide ◽

Rapid Pace

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

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A description of large-scale metabolomics studies: increasing value by combining metabolomics with genome-wide SNP genotyping and transcriptional profiling

Journal of Endocrinology ◽

10.1530/joe-12-0144 ◽

2012 ◽

Vol 215 (1) ◽

pp. 17-28 ◽

Cited By ~ 18

Author(s):

Georg Homuth ◽

Alexander Teumer ◽

Uwe Völker ◽

Matthias Nauck

Keyword(s):

Blood Cells ◽

Large Scale ◽

Genetic Factors ◽

Association Studies ◽

Transcriptional Profiling ◽

Genome Wide Association Studies ◽

Protein Levels ◽

Future Developments ◽

Genome Wide ◽

Metabolome Data

The metabolome, defined as the reflection of metabolic dynamics derived from parameters measured primarily in easily accessible body fluids such as serum, plasma, and urine, can be considered as the omics data pool that is closest to the phenotype because it integrates genetic influences as well as nongenetic factors. Metabolic traits can be related to genetic polymorphisms in genome-wide association studies, enabling the identification of underlying genetic factors, as well as to specific phenotypes, resulting in the identification of metabolome signatures primarily caused by nongenetic factors. Similarly, correlation of metabolome data with transcriptional or/and proteome profiles of blood cells also produces valuable data, by revealing associations between metabolic changes and mRNA and protein levels. In the last years, the progress in correlating genetic variation and metabolome profiles was most impressive. This review will therefore try to summarize the most important of these studies and give an outlook on future developments.

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A deletion in GDF7 is associated with a heritable forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts in cats

10.1101/2020.05.12.091686 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yoshihiko Yu ◽

Erica K. Creighton ◽

Reuben M. Buckley ◽

Leslie A. Lyons ◽

Keyword(s):

Genetic Basis ◽

Association Studies ◽

Homozygosity Mapping ◽

Mammalian Brain ◽

Genome Wide Association Studies ◽

Commissural Axons ◽

Genome Wide ◽

Mixed Breed ◽

Roof Plate ◽

Control Association

AbstractAn inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test, a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing, and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. Obligate carrier cats were heterozygous. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasizes the importance of GDF7 in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant.

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Current knowledge in hypertension genetics: mosaic theory, candidate genes and genome-wide association studies

Arterial’naya Gipertenziya (Arterial Hypertension) ◽

10.18705/1607-419x-2020-26-5-490-500 ◽

2020 ◽

Vol 26 (5) ◽

pp. 490-500

Author(s):

A. O. Konradi

Keyword(s):

Candidate Genes ◽

High Performance ◽

New Technologies ◽

Current Knowledge ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Modern Approach ◽

Genome Wide

The article reviews monogenic forms of hypertension, data on the role of heredity of essential hypertension and candidate genes, as well as genome-wide association studies. Modern approach for the role of genetics is driven by implementation of new technologies and their productivity. High performance speed of new technologies like genome-wide association studies provide data for better knowledge of genetic markers of hypertension. The major goal nowadays for research is to reveal molecular pathways of blood pressure regulation, which can help to move from populational to individual level of understanding of pathogenesis and treatment targets.

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Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE

Clinical Science ◽

10.1042/cs20201033 ◽

2021 ◽

Vol 135 (15) ◽

pp. 1929-1944

Author(s):

Ezekiel Gonzalez-Fernandez ◽

Yedan Liu ◽

Alexander P. Auchus ◽

Fan Fan ◽

Richard J. Roman

Keyword(s):

Cognitive Impairment ◽

Association Studies ◽

Amyloid Β ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Cerebrovascular Risk ◽

Potent Vasoconstrictor ◽

Multiple Drugs ◽

Epidemiology Studies

Abstract The accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer’s disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aβ or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aβ or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood–brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.

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Heritability jointly explained by host genotype and microbiome: will improve traits prediction?

Briefings in Bioinformatics ◽

10.1093/bib/bbaa175 ◽

2020 ◽

Author(s):

Denis Awany ◽

Emile R Chimusa

Keyword(s):

Genetic Variants ◽

Association Studies ◽

Heritability Estimate ◽

Substantial Part ◽

Phenotypic Variance ◽

Genome Wide Association Studies ◽

Host Genotype ◽

Genome Wide ◽

Heritability Estimation

Abstract As we observe the $70$th anniversary of the publication by Robertson that formalized the notion of ‘heritability’, geneticists remain puzzled by the problem of missing/hidden heritability, where heritability estimates from genome-wide association studies (GWASs) fall short of that from twin-based studies. Many possible explanations have been offered for this discrepancy, including existence of genetic variants poorly captured by existing arrays, dominance, epistasis and unaccounted-for environmental factors; albeit these remain controversial. We believe a substantial part of this problem could be solved or better understood by incorporating the host’s microbiota information in the GWAS model for heritability estimation and may also increase human traits prediction for clinical utility. This is because, despite empirical observations such as (i) the intimate role of the microbiome in many complex human phenotypes, (ii) the overlap between genetic variants associated with both microbiome attributes and complex diseases and (iii) the existence of heritable bacterial taxa, current GWAS models for heritability estimate do not take into account the contributory role of the microbiome. Furthermore, heritability estimate from twin-based studies does not discern microbiome component of the observed total phenotypic variance. Here, we summarize the concept of heritability in GWAS and microbiome-wide association studies, focusing on its estimation, from a statistical genetics perspective. We then discuss a possible statistical method to incorporate the microbiome in the estimation of heritability in host GWAS.

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Germline Genetic Factors Influence Outcome of Interferon Alpha Therapy in Polycythemia Vera

Blood ◽

10.1182/blood.2020005792 ◽

2020 ◽

Author(s):

Roland Jäger ◽

Heinz Gisslinger ◽

Elisabeth Fuchs ◽

Edith Bogner ◽

Jelena D. Milosevic Feenstra ◽

...

Keyword(s):

Polycythemia Vera ◽

Interferon Alpha ◽

Genetic Factors ◽

Myeloproliferative Neoplasms ◽

Association Studies ◽

Study Cohort ◽

Molecular Response ◽

Genome Wide Association Studies ◽

Association Analyses ◽

Genome Wide

Interferon alpha (IFNα) based therapies can induce hematologic and molecular responses in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have previously been implicated in differential drug response. We addressed the effect of common germline polymorphisms on hematologic and molecular response (HR/MR) in PV therapy within the PROUD-PV and CONTINUATION-PV studies including 122 patients with PV receiving ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over 36 months follow-up did not reveal any associations at genome-wide significance. Further, we performed targeted association analyses at the interferon lambda 4 (IFNL4) locus, well known for its role in hepatitis C viral clearance and recently reported to influence HR during therapy of myeloproliferative neoplasms. While we did not observe any association of IFNL4 polymorphisms with HR in our study cohort, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair including the protein-coding variants rs368234815/rs117648444) on MR (p=3.91x10-4; OR=10.80; 95%CI:[2.39-69.97]) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of PV patients based on IFNL4 functionality may allow for optimizing patient management during IFNα treatment.

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