The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus

Giuranna, Johanna; Volckmar, Anna‐Lena; Heinen, Anna; Peters, Triinu; Schmidt, Börge; Spieker, Anne; Straub, Helena; Grallert, Harald; Müller, Timo; Antel, Jochen; Haußmann, Ute; Klafki, Hans-Wolfgang; Rui, Liangyou

doi:10.1159/000486962

Cited by 11 publications

(9 citation statements)

References 53 publications

(78 reference statements)

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“…(3) At the locus 16p.11.2 (see locus 26 in Table 1) higher BMI, BF%, WC, HC, HC adjBMI , and higher risk for obesity were negatively associated with intelligence and educational attainment in line with previous evidence (Jacquemont et al, 2011). Genetic variations [SNPs, copy number variants (CNVs), and larger deletions/insertions] at 16p.11.2 have been shown to be associated with developmental delay, ASD, ADHD, schizophrenia, BD, epilepsy, intracranial volume, brain development, congenital anomalies, altered satiety response, energy imbalance, underweight, and morbid obesity (McCarthy et al, 2009;Bochukova et al, 2010;Fernandez et al, 2010;Walters et al, 2010;Jacquemont et al, 2011;Volckmar et al, 2012;Zufferey et al, 2012;Egger et al, 2014;Qureshi et al, 2014;Volckmar et al, 2015;Maillard et al, 2016;Giuranna et al, 2018;Martin-Brevet et al, 2018;Sonderby et al, 2018;Niarchou et al, 2019). The consequences of 16p11.2 CNV and larger deletions and duplications on health are broad (Crawford et al, 2019;Niarchou et al, 2019).…”

Section: Discussionsupporting

confidence: 83%

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study

et al. 2020

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Anthropometric traits and mental disorders or traits are known to be associated clinically and to show genetic overlap. We aimed to identify genetic variants with relevance for mental disorders/traits and either (i) body mass index (or obesity), (ii) body composition, (and/or) (iii) body fat distribution. We performed a look-up analysis of 1,005 genomewide significant SNPs for BMI, body composition, and body fat distribution in 15 mental disorders/traits. We identified 40 independent loci with one or more SNPs fulfilling our threshold significance criterion (P < 4.98 × 10 −5) for the mental phenotypes. The majority of loci was associated with schizophrenia, educational attainment, and/or intelligence. Fewer associations were found for bipolar disorder, neuroticism, attention deficit/hyperactivity disorder, major depressive disorder, depressive symptoms, and well-being. Unique associations with measures of body fat distribution adjusted for BMI were identified at five loci only. To investigate the potential causality between body fat distribution and schizophrenia, we performed two-sample Mendelian randomization analyses. We found no causal effect of body fat distribution on schizophrenia and vice versa. In conclusion, we identified 40 loci which may contribute to genetic overlaps between mental disorders/traits and BMI and/or shape related phenotypes. The majority of loci identified for body composition overlapped with BMI loci, thus suggesting pleiotropic effects.

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Section: Discussionsupporting

confidence: 83%

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study

et al. 2020

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“…These data provide excellent examples of how to integrate GWAS, eQTL, and ATAC-seq data to identify functional variants at GWAS loci. Further experiments are needed to determine if these variants are the only functional variants at each locus, as we also observed allelic differences in protein binding for a second variant overlapping an ATAC-seq peak at the SH2B1 locus (Figure S5B) and others have suggested different functional variants at this locus,(Giuranna et al 2018; Volckmar et al 2012) and which gene(s) are contributing to obesity risk.…”

Section: Discussionmentioning

confidence: 91%

Open Chromatin Profiling in Adipose Tissue Marks Genomic Regions with Functional Roles in Cardiometabolic Traits

Cannon¹,

Currin²,

Young

et al. 2019

G3 Genes|Genomes|Genetics

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Identifying the regulatory mechanisms of genome-wide association study (GWAS) loci affecting adipose tissue has been restricted due to limited characterization of adipose transcriptional regulatory elements. We profiled chromatin accessibility in three frozen human subcutaneous adipose tissue needle biopsies and preadipocytes and adipocytes from the Simpson Golabi-Behmel Syndrome (SGBS) cell strain using an assay for transposase-accessible chromatin (ATAC-seq). We identified 68,571 representative accessible chromatin regions (peaks) across adipose tissue samples (FDR < 5%). GWAS loci for eight cardiometabolic traits were enriched in these peaks ( P < 0.005), with the strongest enrichment for waist-hip ratio. Of 110 recently described cardiometabolic GWAS loci colocalized with adipose tissue eQTLs, 59 loci had one or more variants overlapping an adipose tissue peak. Annotated variants at the SNX10 waist-hip ratio locus and the ATP2A1-SH2B1 body mass index locus showed allelic differences in regulatory assays. These adipose tissue accessible chromatin regions elucidate genetic variants that may alter adipose tissue function to impact cardiometabolic traits.

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“…19 A number of genetic studies on humans have suggested that any deficiencies in the insulin-signalling pathway could result from either mutation in the insulin receptor within the SH2B1 gene, or the existence of antibodies against either the insulin receptor or insulin itself, are rarely causing insulin resistance. 20,21 In this study, no effect of population stratification was encountered due to the relative homogeneity of the Jordanian Arab population. This provides useful benefits to genetic studies as smaller numbers of multiple variations occurred in the genes that are responsible for the observed phenotypes, and expected to be identified in populations that are more homogeneous.…”

Section: Discussionmentioning

confidence: 71%

<p>Genetic Association of <em>SH2B1</em> Gene Polymorphisms in Jordanian Arab Patients with Type 2 Diabetes Mellitus</p>

AL-Eitan

Aman

Alkhatib

et al. 2020

DMSO

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Objective: To investigate the genotypic and allelic association of Src homology 2 B adapter protein 1 (SH2B1) gene polymorphisms with type 2 diabetes mellitus (T2DM) in Jordanian patients. Patients and Methods: Three hundred patients were screened, but only 200 adult Jordanian patients diagnosed with T2DM (53.5% male and 46.5% female) have participated in this study. Blood samples were collected from both patients and healthy individuals for DNA extraction according to well-established procedures. Exon 1 and exon 9 of the SH2B1 gene were sequenced using an efficient and sensitive DNA sequencing method in order to identify specific single nucleotide polymorphisms (SNPs) in the SH2B1 gene associated with T2DM. Genetic and haplotype correlation analysis was performed for the chosen SNPs to detect any association if existent. In addition, SNPStats Web Tool and Hardy-Weinberg equilibrium (HWE) analyses for the genotype distribution were used. The significance was determined according to the P-value, and the level of significance taken as P < 0.05. The normality of the data distribution was statically analysed by the Shapiro-Wilk test with a P-value >0.05. Also, the patient's characteristics and clinical data about all participants were mentioned. Results: Two novel variations were present in the SH2B1 gene in Jordanian patients with T2DM: c.827C>G and c.2026G>A, and previously reported five SNPs: rs146946750, rs565131715, rs370302573, rs143212778, rs200470848. Our results showed a strong genetic association of rs565131715 SNP polymorphism within the SH2B1 gene in T2DM patients (χ 2 test, P < 0.001). Additionally, rs143212778 SNP presented a genetic correlation with T2DM patients (χ 2 test, P = 0.035) as compared to control individuals. GTACG haplotype of SH2B1 has a highly significant association with responders (P< 0.0001). Conclusion: Our findings indicated a strong association between the rs565131715 polymorphism and the risk of T2DM among the Jordanian population. Moreover, our data showed that the rs143212778 polymorphism significantly elevated the danger of T2DM among this population. This study reveals the first data regarding the SH2B1 gene polymorphisms in Jordanian patients of Arab descent with diabetes.

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The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus

Cited by 11 publications

References 53 publications

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study

Open Chromatin Profiling in Adipose Tissue Marks Genomic Regions with Functional Roles in Cardiometabolic Traits

<p>Genetic Association of <em>SH2B1</em> Gene Polymorphisms in Jordanian Arab Patients with Type 2 Diabetes Mellitus</p>

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