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

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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Genome-Wide Association Study of Body Fat Distribution identifies Novel Adiposity Loci and Sex-Specific Genetic Effects

10.1101/207498 ◽

2017 ◽

Author(s):

Mathias Rask-Andersen ◽

Torgny Karlsson ◽

Weronica E Ek ◽

Åsa Johansson

Keyword(s):

Body Fat ◽

Genome Wide Association Study ◽

Metabolic Diseases ◽

Association Studies ◽

Fat Distribution ◽

Body Fat Distribution ◽

The Body ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

Body mass and body fat composition are of clinical interest due to their links to cardiovascular- and metabolic diseases. Fat stored in the trunk has been suggested as more pathogenic compared to fat stored in other compartments of the body. In this study, we performed genome-wide association studies (GWAS) for the proportion of body fat distributed to the arms, legs and trunk estimated from segmental bio-electrical impedance analysis (sBIA) for 362,499 individuals from the UK Biobank. A total of 97 loci, were identified to be associated with body fat distribution, 40 of which have not previously been associated with an anthropometric trait. A high degree of sex-heterogeneity was observed and associations were primarily observed in females, particularly for distribution of fat to the legs or trunk. Our findings also implicate that body fat distribution in females involves mesenchyme derived tissues and cell types, female endocrine tissues a well as several enzymatically active members of the ADAMTS family of metalloproteinases, which are involved in extracellular matrix maintenance and remodeling.

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Genetics and Management of the Patient with Orofacial Cleft

Plastic Surgery International ◽

10.1155/2012/782821 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 5

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.

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Investigating the role of insulin in increased adiposity: Bi-directional Mendelian randomization study

10.1101/155739 ◽

2017 ◽

Cited By ~ 5

Author(s):

RC Richmond ◽

KH Wade ◽

L Corbin ◽

J Bowden ◽

G Hemani ◽

...

Keyword(s):

Large Scale ◽

Causal Effect ◽

Association Studies ◽

The Body ◽

Genome Wide Association Studies ◽

Fasting Insulin ◽

Insulin Levels ◽

Genome Wide ◽

Weighted Median ◽

High Degree

AbstractInsulin may serve as a key causal agent which regulates fat accumulation in the body. Here we assessed the causal relationship between fasting insulin and adiposity using publicly-available results from two large-scale genome-wide association studies for body mass index and fasting insulin levels in a two-sample, bidirectional Mendelian Randomized approach. This approach is only valid on the condition that the two instruments are independent of one another. In analysis excluding overlapping loci, there was an increase of 0.20 (0.17, 0.23) log pmol/L fasting insulin per SD increase in BMI (P= 2.80 x 10−36), while there was a null effect of fasting insulin on BMI, with a 0.01 (−0.39, 0.38) SD decrease in BMI per log pmol/L increase in fasting insulin (P= 0.98). Furthermore, a high degree of heterogeneity in the causal estimates was obtained from the insulin-related variants, which may be attributed to varying mechanisms of action of the insulin-associated variants. Results were largely consistent when an Egger regression technique and weighted median and mode estimators were applied. Findings suggest that the positive correlation between adiposity and fasting insulin levels are at least in part explained by the causal effect of adiposity on increasing insulin, rather than vice versa.

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Parkinson’s Disease Associated with GBA Gene Mutations: Molecular Aspects and Potential Treatment Approaches

Acta Naturae ◽

10.32607/actanaturae.11031 ◽

2021 ◽

Vol 13 (2) ◽

pp. 70-78

Author(s):

Konstantin A. Senkevich ◽

Alena E. Kopytova ◽

Tatiana S. Usenko ◽

Anton K. Emelyanov ◽

Sofya N. Pchelina

Keyword(s):

Association Studies ◽

Gene Mutations ◽

Genome Wide Association Studies ◽

Gene Encoding ◽

Parkinsons Disease ◽

Genome Wide ◽

Genetic Mechanisms ◽

Gba Gene ◽

Intensive Investigation ◽

Molecular Aspects

Parkinsons disease (PD) is a multifactorial neurodegenerative disease. To date, genome-wide association studies have identified more than 70 loci associated with the risk of PD. Variants in the GBA gene encoding glucocerebrosidase are quite often found in PD patients in all populations across the world, which justifies intensive investigation of this gene. A number of biochemical features have been identified in patients with GBA-associated Parkinsons disease (GBA-PD). In particular, these include decreased activity of glucocerebrosidase and accumulation of the glucosylceramide substrate. These features were the basis for putting forward a hypothesis about treatment of GBA-PD using new strategies aimed at restoring glucocerebrosidase activity and reducing the substrate concentration. This paper discusses the molecular and genetic mechanisms of GBA-PD pathogenesis and potential approaches to the treatment of this form of the disease.

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Genome-Wide Association Studies for Milk Somatic Cell Score in Romanian Dairy Cattle

Genes ◽

10.3390/genes12101495 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1495

Author(s):

Daniela Elena Ilie ◽

Alexandru Eugeniu Mizeranschi ◽

Ciprian Valentin Mihali ◽

Radu Ionel Neamț ◽

George Vlad Goilean ◽

...

Keyword(s):

Dairy Cattle ◽

Somatic Cell ◽

Association Studies ◽

Somatic Cell Score ◽

The Body ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Cattle Breeds ◽

Multiple Loci ◽

Genome Wide

Mastitis is one of the most frequently encountered diseases in dairy cattle, negatively affecting animal welfare and milk production. For this reason, contributions to understanding its genomic architecture are of great interest. Genome-wide association studies (GWAS) have identified multiple loci associated with somatic cell score (SCS) and mastitis in cattle. However, most of the studies have been conducted in different parts of the world on various breeds, and none of the investigations have studied the genetic architecture of mastitis in Romanian dairy cattle breeds up to this point in time. In this study, we report the first GWAS for SCS in dairy cattle breeds from Romania. For GWAS, we used an Axiom Bovine v3 SNP-chip (>63,000 Single Nucleotide Polymorphism -SNPs) and 33,330 records from 690 cows belonging to Romanian Spotted (RS) and Romanian Brown (RB) cattle. The results found one SNP significantly associated with SCS in the RS breed and 40 suggestive SNPs with −log10 (p) from 4 to 4.9 for RS and from 4 to 5.4 in RB. From these, 14 markers were located near 12 known genes (AKAP8, CLHC1, MEGF10, SATB2, GATA6, SPATA6, COL12A1, EPS8, LUZP2, RAMAC, IL12A and ANKRD55) in RB cattle, 3 markers were close to ZDHHC19, DAPK1 and MMP7 genes, while one SNP overlapped the HERC3 gene in RS cattle. Four genes (HERC3, LUZP2, AKAP8 and MEGF10) associated with SCS in this study were previously reported in different studies. The most significant SNP (rs110749552) associated with SCS was located within the HERC3 gene. In both breeds, the SNPs and position of association signals were distinct among the three parities, denoting that mastitis is controlled by different genes that are dependent according to parity. The current results contribute to an expansion in the body of knowledge regarding the proportion of genetic variability explained by SNPs for SCS in dairy cattle.

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Genes related to the white face colour pattern in eight Russian cattle breeds

Vavilov Journal of Genetics and Breeding ◽

10.18699/vj18.350 ◽

2018 ◽

Vol 22 (2) ◽

pp. 217-223 ◽

Cited By ~ 2

Author(s):

N. S. Yudin ◽

N. M. Belonogova ◽

D. M. Larkin

Keyword(s):

Association Studies ◽

Coat Colour ◽

The Body ◽

Whole Body ◽

Colour Pattern ◽

Genome Wide Association Studies ◽

Cattle Breeds ◽

Genome Wide ◽

White Face ◽

White Colour

One of the major effects of domestication is change of animal coat colour to up to complete white colour of the whole body. It is possible that white colour of livestock animals had aesthetic significance for humans as well. The first step towards detection of genes and mutations controlling white colouring in animals is the genome-wide association studies. These studies, however, have not been done for the cattle breeds native to the Russian Federation. The aim of this study was therefore to identify genomic intervals and candidate genes that could be responsible for white face colouring in eight Russian cattle breeds. The data on genome-wide genotyping of 131,709 high-quality single nucleotide polymorphisms (SNPs) on 148 animas have been used in the program EMMAX. Association analysis has been performed using two related phenotypes: a) the white face with the rest of the body of any colour and b) white face with the rest of the body of different (non-white) colour. In the first case, the only statistically significant marker found was the SNP BovineHD0500019319 located on cattle chromosome (BTA) 5. The same SNP was the most significant within the cluster of three SNPs on BTA5: 68,803,879–69,365,854 associated also with the second phenotype. Five genes were found within this interval in the cattle genome, out of which the most likely functional candidate was SLC41A2, with the SNP BovineHD0500019319 found within its intronic sequence. SLC41A2 encodes a magnesium transporter protein. However, the function of this gene is not well established. Other members of this gene family are the key genes controlling differences in human skin and animal coat colour. Additional significant association signals with the second phenotype have been detected in BTA 1–4, 6–15, 18, 19, 24, 27, and 29. Overall, 37 genomic intervals have been detected associated with white face colouring in eight Russian native cattle breeds.

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Identification of GLUT12/SLC2A12 as a urate transporter that regulates the blood urate level in hyperuricemia model mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2006958117 ◽

2020 ◽

Vol 117 (31) ◽

pp. 18175-18177

Author(s):

Yu Toyoda ◽

Tappei Takada ◽

Hiroshi Miyata ◽

Hirotaka Matsuo ◽

Hidetoshi Kassai ◽

...

Keyword(s):

Uric Acid ◽

Physiological Function ◽

Association Studies ◽

Regulatory System ◽

The Body ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Functional Assays ◽

Urate Transporter ◽

Genome Wide

Recent genome-wide association studies have revealed some genetic loci associated with serum uric acid levels and susceptibility to gout/hyperuricemia which contain potential candidates of physiologically important urate transporters. One of these novel loci is located upstream ofSGK1andSLC2A12, suggesting that variations in these genes increase the risks of hyperuricemia and gout. We herein focused onSLC2A12encoding a transporter, GLUT12, the physiological function of which remains unclear. As GLUT12 belongs to the same protein family as a well-recognized urate transporter GLUT9, we hypothesized that GLUT12 mediates membrane transport of urate. Therefore, we conducted functional assays and analyzedGlut12knockout hyperuricemia model mice, generated using the CRISPR-Cas9 system. Our results revealed that GLUT12 acts as a physiological urate transporter and its dysfunction elevates the blood urate concentration. This study provides insights into the deeper understanding of the urate regulatory system in the body, which is also important for pathophysiology of gout/hyperuricemia.

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Developmental aspects of cardiac arrhythmias

10.1093/med/9780198757269.003.0027 ◽

2018 ◽

Author(s):

Alex V. Postma ◽

David Sedmera ◽

Frantisek Vostarek ◽

Vincent M. Christoffels ◽

Connie R. Bezzina

Keyword(s):

Regional Differences ◽

Causal Relation ◽

Association Studies ◽

The Body ◽

Developmental Changes ◽

Genome Wide Association Studies ◽

Electrophysiological Properties ◽

Functional Aspects ◽

Genome Wide ◽

Insight Into

The rhythmic and synchronized contraction of atria and ventricles is essential for efficient pumping of blood throughout the body. This process relies on the proper generation and conduction of the cardiac electrical impulse. Electrophysiological properties differ in various regions of the heart, revealing intrinsic heterogeneities rooted, at least in part, in regional differences in expression of ion channel and gap junction subunit genes. A causal relation between transcription factors and such regionalized gene expression has been established. Abnormal cardiac electrical function and arrhythmias in the postnatal heart may stem from a developmental changes in gene regulation. Genome-wide association studies have provided strong evidence that common genetic variation at developmental gene loci modulates electrocardiographic indices of conduction and repolarization and susceptibility to arrhythmia. Functional aspects are illustrated by description of selected prenatally occurring arrhythmias and their possible mechanisms. We also discuss recent findings and provide background insight into these complex mechanisms.

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Genetics and pain in childhood

Oxford Textbook of Pediatric Pain ◽

10.1093/med/9780198818762.003.0009 ◽

2021 ◽

pp. 79-86

Author(s):

Jeffrey S. Mogil

Keyword(s):

Candidate Gene ◽

Association Studies ◽

Single Gene ◽

Gene Mutations ◽

Twin Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Pediatric Pain ◽

Genome Wide ◽

Pediatric Populations

Genomic and other “omic” approaches are now routinely applied to the study of pain. Some of these investigations have utilized pediatric populations. This review describes what is currently known about the heritability of pain in children (from twin studies), genes relevant to pain in children (from single-gene mutations, candidate gene, and genome-wide association studies), and the application of newer techniques, such as epigenomics, to pediatric pain.

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Post-GWAS knowledge gap: the how, where, and when

npj Parkinson s Disease ◽

10.1038/s41531-020-00125-y ◽

2020 ◽

Vol 6 (1) ◽

Cited By ~ 1

Author(s):

Steven E. Pierce ◽

Alix Booms ◽

Jordan Prahl ◽

Edwin J. C. van der Schans ◽

Trevor Tyson ◽

...

Keyword(s):

Association Studies ◽

Single Gene ◽

Large Population ◽

Gene Mutations ◽

Mendelian Inheritance ◽

Effector Proteins ◽

Large Set ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Small Effect Size

Abstract Genetic risk for complex diseases very rarely reflects only Mendelian-inherited phenotypes where single-gene mutations can be followed in families by linkage analysis. More commonly, a large set of low-penetrance, small effect-size variants combine to confer risk; they are normally revealed in genome-wide association studies (GWAS), which compare large population groups. Whereas Mendelian inheritance points toward disease mechanisms arising from the mutated genes, in the case of GWAS signals, the effector proteins and even general risk mechanism are mostly unknown. Instead, the utility of GWAS currently lies primarily in predictive and diagnostic information. Although an amazing body of GWAS-based knowledge now exists, we advocate for more funding towards the exploration of the fundamental biology in post-GWAS studies; this research will bring us closer to causality and risk gene identification. Using Parkinson’s Disease as an example, we ask, how, where, and when do risk loci contribute to disease?

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