A novel gene THSD7A is associated with obesity

Nizamuddin, Sheikh; Govindaraj, Periyasamy; Saxena, Sandeep; Kashyap, Manju; Mishra, Anshuman; Singh, Shashi; Rotti, Harish; Raval, Ritu; Nayak, Jayakrishna; Bhat, Balakrishna K; Prasanna, B V; Dhumal, Vikram Ram; Bhale, Sameer; Joshi, Kalpana; Dedge, Amrish P; Bharadwaj, Ramachandra; Gangadharan, G G; Nair, Sreekumaran; Gopinath, P. M.; Patwardhan, Bhushan; Kondaiah, Paturu; Satyamoorthy, Kapaettu; Valiathan, Manna; Thangaraj, Kumarasamy

doi:10.1038/ijo.2015.144

Cited by 15 publications

(6 citation statements)

References 28 publications

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“…A locus on chromosome 7 with the lead SNP rs78495856 ( p = 4.9 × 10 −7 ) is in an intron of the THSD7A gene. A previous genome-wide association study of BMI found an association with THSD7A ( 25 ).…”

Section: Resultsmentioning

confidence: 88%

Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort

et al. 2021

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This study is the first genetically-informed investigation of avoidant/restrictive food intake disorder (ARFID), an eating disorder that profoundly impacts quality of life for those affected. ARFID is highly comorbid with autism, and we provide the first estimate of its prevalence in a large and phenotypically diverse autism cohort (a subsample of the SPARK study, N = 5,157 probands). This estimate, 21% (at a balanced accuracy 80%), is at the upper end of previous estimates from studies based on clinical samples, suggesting under-diagnosis and potentially lack of awareness among caretakers and clinicians. Although some studies suggest a decrease of disordered eating symptoms by age 6, our estimates indicate that up to 17% (at a balanced accuracy 87%) of parents of autistic children are also at heightened risk for ARFID, suggesting a lifelong risk for disordered eating. We were also able to provide the first estimates of narrow-sense heritability (h2) for ARFID risk, at 0.45. Genome-wide association revealed a single hit near ZSWIM6, a gene previously implicated in neurodevelopmental conditions. While, the current sample was not well-powered for GWAS, effect size and heritability estimates allowed us to project the sample sizes necessary to more robustly discover ARFID-linked loci via common variants. Further genetic analysis using polygenic risk scores (PRS) affirmed genetic links to autism as well as neuroticism and metabolic syndrome.

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Section: Resultsmentioning

confidence: 88%

Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort

et al. 2021

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“…rs12154393711,210,9313.8280.7623.06E-060.12740.30926.86E-06 NDUFA4 Candidate gene for role in cellular aging in dental follicle stem cells [57]. THSD7A Obesity candidate gene [58]. rs6947348726,383,7484.6150.7991.70E-070.38090.4373.35E-06 MIR148 Involved in dental stem cells [59].…”

Section: Resultsmentioning

confidence: 99%

“…The locus chr16:28719857 ( p -value 4.36 × 10 − 6 ) contains genes associated with body fat percentage ( APOBR ) [67] and BMI ( SH2B1 ) [68], and rs12154393 (p-value 3.06 × 10–6) contains THSD7A , a candidate gene for obesity [58].…”

Section: Discussionmentioning

confidence: 99%

Pilot GWAS of caries in African-Americans shows genetic heterogeneity

Orlova¹,

Carlson

Lee

et al. 2019

BMC Oral Health

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Background Dental caries is the most common chronic disease in the US and disproportionately affects racial/ethnic minorities. Caries is heritable, and though genetic heterogeneity exists between ancestries for a substantial portion of loci associated with complex disease, a genome-wide association study (GWAS) of caries specifically in African Americans has not been performed previously. Methods We performed exploratory GWAS of dental caries in 109 African American adults (age > 18) and 96 children (age 3–12) from the Center for Oral Health Research in Appalachia (COHRA1 cohort). Caries phenotypes (DMFS, DMFT, dft, and dfs indices) assessed by dental exams were tested for association with 5 million genotyped or imputed single nucleotide polymorphisms (SNPs), separately in the two age groups. The GWAS was performed using linear regression with adjustment for age, sex, and two principal components of ancestry. A maximum of 1 million adaptive permutations were run to determine empirical significance. Results No loci met the threshold for genome-wide significance, though some of the strongest signals were near genes previously implicated in caries such as antimicrobial peptide DEFB1 (rs2515501; p = 4.54 × 10− 6) and TUFT1 (rs11805632; p = 5.15 × 10− 6). Effect estimates of lead SNPs at suggestive loci were compared between African Americans and Caucasians (adults N = 918; children N = 983). Significant (p < 5 × 10− 8) genetic heterogeneity for caries risk was found between racial groups for 50% of the suggestive loci in children, and 12–18% of the suggestive loci in adults. Conclusions The genetic heterogeneity results suggest that there may be differences in the contributions of genetic variants to caries across racial groups, and highlight the critical need for the inclusion of minorities in subsequent and larger genetic studies of caries in order to meet the goals of precision medicine and to reduce oral health disparities.

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“…Genome-wide association studies (GWAS) have linked several single nucleotide polymorphisms (SNPs) in WWOX with obesity [21], [22] and T2D [23], [24]. To systematically study the role of WWOX in MetS, we reanalyzed GWAS datasets (n = 27) from the Type 2 Diabetes Knowledge Portal website (www.type2diabetesgenetics.org).…”

Section: Resultsmentioning

confidence: 99%

“…Over the last decade, many GWAS studies have reported several genetic variants in WWOX as among the most significant SNPs and variants associated with obesity and T2D [22], [24]. However, a direct role of WWOX involvement in metabolic disorders is unclear.…”

Section: Discussionmentioning

confidence: 99%

WWOX somatic ablation in skeletal muscles alters glucose metabolism

Abu-Remaileh

Akkawi

et al. 2019

Molecular Metabolism

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Objective WWOX , a well-established tumor suppressor, is frequently lost in cancer and plays important roles in DNA damage response and cellular metabolism. Methods We re-analyzed several genome-wide association studies (GWAS) using the Type 2 Diabetes Knowledge Portal website to uncover WWOX's association with metabolic syndrome (MetS). Using several engineered mouse models, we studied the effect of somatic WWOX loss on glucose homeostasis. Results Several WWOX variants were found to be strongly associated with MetS disorders. In mouse models, somatic ablation of Wwox in skeletal muscle ( Wwox ΔSKM ) results in weight gain, glucose intolerance, and insulin resistance. Furthermore, Wwox ΔSKM mice display reduced amounts of slow-twitch fibers, decreased mitochondrial quantity and activity, and lower glucose oxidation levels. Mechanistically, we found that WWOX physically interacts with the cellular energy sensor AMP-activated protein kinase (AMPK) and that its loss is associated with impaired activation of AMPK, and with significant accumulation of the hypoxia inducible factor 1 alpha (HIF1α) in SKM. Conclusions Our studies uncover an unforeseen role of the tumor suppressor WWOX in whole-body glucose homeostasis and highlight the intimate relationship between cancer progression and metabolic disorders, particularly obesity and type-2 diabetes. Subject areas Genetics, Metabolic Syndrome, Diabetes.

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A novel gene THSD7A is associated with obesity

Cited by 15 publications

References 28 publications

Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort

Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort

Pilot GWAS of caries in African-Americans shows genetic heterogeneity

WWOX somatic ablation in skeletal muscles alters glucose metabolism

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