scholarly journals Genetics of Progressive Supranuclear Palsy: A Review

2020 ◽  
pp. 1-13
Author(s):  
Yafei Wen ◽  
Yafang Zhou ◽  
Bin Jiao ◽  
Lu Shen
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Association Studies ◽  
Age At Onset ◽  
Gene Mutations ◽  
Genome Wide Association Studies ◽  
Genetic Studies ◽  
Genome Wide ◽  
Potential Association ◽  
Rare Genetic Variants ◽  
Vertical Supranuclear Gaze Palsy

Progressive supranuclear palsy (PSP) is an atypical parkinsonism with prominent 4R-tau neuropathology, and the classical clinical phenotype is characterized by vertical supranuclear gaze palsy, unprovoked falls, akinetic-rigid syndrome and cognitive decline. Though PSP is generally regarded as sporadic, there is increasing evidence suggesting that a series of common and rare genetic variants impact on sporadic and familial forms of PSP. To date, more than 10 genes have been reported to show a potential association with PSP. Among these genes, the microtubule-associated protein tau (MAPT) is the risk locus with the strongest effect size on sporadic PSP in the case-control genome-wide association studies (GWAS). Additionally, MAPT mutations are the most common cause of familial PSP while the leucine-rich repeat kinase 2 (LRRK2) is a rare monogenic cause of PSP, and several other gene mutations may mimic the PSP phenotype, like the dynactin subunit 1 (DCTN1). In total, 15 MAPT mutations have been identified in cases with PSP, and the mean age at onset is much earlier than in cases carrying LRRK2 or DCTN1 mutations. GWAS have further identified several risk loci of PSP, proposing molecular pathways related to PSP. The present review focused on genetic studies on PSP and summarized genetic factors of PSP, which may help to elucidate the underlying pathogenesis and provide new perspectives for therapeutic strategies.

scholarly journals Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations

2020 ◽  
Vol 126 (12) ◽  
pp. 1816-1840
Author(s):  
Lindsay Fernández-Rhodes ◽  
Kristin L. Young ◽  
Adam G. Lilly ◽  
Laura M. Raffield ◽  
Heather M. Highland ◽  
...  
Keyword(s):  
Public Health ◽  
Precision Medicine ◽  
Association Studies ◽  
Evidence Base ◽  
Cardiometabolic Disease ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Genetic Studies ◽  
Genome Wide ◽  
Current Variation

Genome-wide association studies have revolutionized our understanding of the genetic underpinnings of cardiometabolic disease. Yet, the inadequate representation of individuals of diverse ancestral backgrounds in these studies may undercut their ultimate potential for both public health and precision medicine. The goal of this review is to describe the imperativeness of studying the populations who are most affected by cardiometabolic disease, to the aim of better understanding the genetic underpinnings of the disease. We support this premise by describing the current variation in the global burden of cardiometabolic disease and emphasize the importance of building a globally and ancestrally representative genetics evidence base for the identification of population-specific variants, fine-mapping, and polygenic risk score estimation. We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies. Despite these challenges, we conclude that additional, unprecedented opportunities lie ahead for public health genomics and the realization of precision medicine, provided that the gap in diversity can be systematically addressed. Achieving this goal will require concerted efforts by social, academic, professional and regulatory stakeholders and communities, and these efforts must be based on principles of equity and social justice.

scholarly journals Atrial fibrillation—a complex polygenetic disease

2020 ◽  
Author(s):  
Julie H. Andersen ◽  
Laura Andreasen ◽  
Morten S. Olesen
Keyword(s):  
Atrial Fibrillation ◽  
Rare Variants ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Research Field ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Genome Wide ◽  
Transcription Factor Genes ◽  
Rare Genetic Variants

AbstractAtrial fibrillation (AF) is the most common type of arrhythmia. Epidemiological studies have documented a substantial genetic component. More than 160 genes have been associated with AF during the last decades. Some of these were discovered by classical linkage studies while the majority relies on functional studies or genome-wide association studies. In this review, we will evaluate the genetic basis of AF and the role of both common and rare genetic variants in AF. Rare variants in multiple ion-channel genes as well as gap junction and transcription factor genes have been associated with AF. More recently, a growing body of evidence has implicated structural genes with AF. An increased burden of atrial fibrosis in AF patients compared with non-AF patients has also been reported. These findings challenge our traditional understanding of AF being an electrical disease. We will focus on several quantitative landmark papers, which are transforming our understanding of AF by implicating atrial cardiomyopathies in the pathogenesis. This new AF research field may enable better diagnostics and treatment in the future.

Two-Stage Procedures for the Identification of Gene × Environment and Gene × Gene Interactions in Genome-Wide Association Studies

2016 ◽  
Author(s):  
Charles Kooperberg ◽  
James Y. Dai ◽  
Li Hsu
Keyword(s):  
Association Studies ◽  
Gene Interaction ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Two Stage ◽  
Genetic Studies ◽  
Gene Environment ◽  
Genome Wide ◽  
Sequencing Studies ◽  
Generation Sequencing

Genome-wide association studies and next generation sequencing studies offer us an unprecedented opportunity to study the genetic etiology of diseases and other traits. Over the last few years, many replicated associations between SNPs and traits have been published. It is of particular interest to identify how genes may interact with environmental factors and other genes. In this chapter, we show that a two-stage approach, where in the first stage SNPs are screened for their potential to be involved in interactions, and interactions are then tested only among SNPs that pass the screening can greatly enhance power for detecting gene-environment and gene-gene interaction in large genetic studies compared to the tests without screening.

scholarly journals The UMOD Locus: Insights into the Pathogenesis and Prognosis of Kidney Disease

2017 ◽  
Vol 29 (3) ◽  
pp. 713-726 ◽  
Author(s):  
Olivier Devuyst ◽  
Cristian Pattaro
Keyword(s):  
Kidney Disease ◽  
Kidney Diseases ◽  
Association Studies ◽  
Biochemical Properties ◽  
Genome Wide Association Studies ◽  
Genetic Studies ◽  
Rare Mutations ◽  
Genome Wide ◽  
Genomic Regions ◽  
Insight Into

The identification of genetic factors associated with kidney disease has the potential to provide critical insights into disease mechanisms. Genome-wide association studies have uncovered genomic regions associated with renal function metrics and risk of CKD. UMOD is among the most outstanding loci associated with CKD in the general population, because it has a large effect on eGFR and CKD risk that is consistent across different ethnic groups. The relevance of UMOD for CKD is clear, because the encoded protein, uromodulin (Tamm–Horsfall protein), is exclusively produced by the kidney tubule and has specific biochemical properties that mediate important functions in the kidney and urine. Rare mutations in UMOD are the major cause of autosomal dominant tubulointerstitial kidney disease, a condition that leads to CKD and ESRD. In this brief review, we use the UMOD paradigm to describe how population genetic studies can yield insight into the pathogenesis and prognosis of kidney diseases.

scholarly journals Genetics and Management of the Patient with Orofacial Cleft

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Luciano Abreu Brito ◽  
Joanna Goes Castro Meira ◽  
Gerson Shigeru Kobayashi ◽  
Maria Rita Passos-Bueno
Keyword(s):  
Cleft Lip ◽  
Association Studies ◽  
Single Gene ◽  
Gene Mutations ◽  
Deletion Syndrome ◽  
Genome Wide Association Studies ◽  
Genetic Causes ◽  
Complex Disorder ◽  
Facial Defect ◽  
Genome Wide

Cleft lip or palate (CL/P) is a common facial defect present in 1 : 700 live births and results in substantial burden to patients. There are more than 500 CL/P syndromes described, the causes of which may be single-gene mutations, chromosomopathies, and exposure to teratogens. Part of the most prevalent syndromic CL/P has known etiology. Nonsyndromic CL/P, on the other hand, is a complex disorder, whose etiology is still poorly understood. Recent genome-wide association studies have contributed to the elucidation of the genetic causes, by raising reproducible susceptibility genetic variants; their etiopathogenic roles, however, are difficult to predict, as in the case of the chromosomal region 8q24, the most corroborated locus predisposing to nonsyndromic CL/P. Knowing the genetic causes of CL/P will directly impact the genetic counseling, by estimating precise recurrence risks, and the patient management, since the patient, followup may be partially influenced by their genetic background. This paper focuses on the genetic causes of important syndromic CL/P forms (van der Woude syndrome, 22q11 deletion syndrome, and Robin sequence-associated syndromes) and depicts the recent findings in nonsyndromic CL/P research, addressing issues in the conduct of the geneticist.

scholarly journals Melanocortin Pathways: Suppressed and Stimulated Melanocortin-4 Receptor (MC4R)

2020 ◽  
pp. S245-S254
Author(s):  
V. HAINER ◽  
I. ALDHOON HAINEROVÁ ◽  
M. KUNEŠOVÁ ◽  
R. TAXOVÁ BRAUNEROVÁ ◽  
H. ZAMRAZILOVÁ ◽  
...  
Keyword(s):  
Association Studies ◽  
Gene Mutations ◽  
The Body ◽  
Genome Wide Association Studies ◽  
New Horizons ◽  
Mc4r Gene ◽  
Melanocortin 4 Receptor ◽  
Cardiovascular Side Effects ◽  
Genome Wide ◽  
Melanocortin Signaling

Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.

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