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Approved Research

The relationship of low-frequency gain-of-function missense variants in LGR4 and the onset of obesity.

Principal Investigator: Dr Jiqiu Wang
Approved Research ID: 70579
Approval date: March 30th 2022

Lay summary

Aims:  To investigate the relationship between the variants of LGR4 and fat-related clinical characteristics in humans.

Scientific rationale:  Central obesity is characterized by abdominal visceral fat accumulation and abundant evidence has shown that central obesity is an important indicator of metabolic disorders. Therefore, identifying the causal factors leading to central obesity might provide valuable clues for the prevention and treatment of obesity-related complications in humans.

Project duration: 12 months.

Public health impact: Providing new insights into obesity-candidate genetic variants in abdominal fat accumulation, pointing to novel possibilities for more effective prevention and clinical intervention of obesity-related diseases by targeting LGR4.

Scope extension:

In past few years, our team focused on a low-frequency gain-of-function missense variants in LGR4 (rs149204548), which is positively associated with central obesity according to our cohort studys. In detail, female subjects carrying LGR4A750T mutation shown a higher waist-hip ratio while males with LGR4A750T mutation have a lower Waist-hip ratio. To further elucidate the causal relationship of LGR4A750T and obesity, we established humanized LGR4A750T mutant mice (point mutation knockin model) using the crisper/cas9 strategy. Consistently, female mice with heterozygous and homozygous Lgr4A750T mice exhibits a higher body weight gain, which is not observed in male mice. Meanwhile, with micro-CT measurement, we also found an increased bone mineral density in male LGR4A750T mice but not in female LGR4A750T mice.

However, we did not find the association LGR4A750T with bone density in our pilot cohort, probably due to the relatively small sample-size. In this aspect, we would like to apply to get access to UKbiobank WES data, to further explore the clinical outcomes LGR4A750T carriers in the obesity and bone density phenotypes. It would be so meaningful for understanding the role of this important GPCR in the etiology and potential treatment of obesity and osteoporosis patients.

Our Genetics of Obesity in Chinese Youngs (GOCY) cohort, focusing on young individuals (age < 30 years) with obesity (BMI > 30 kg/m2), have identified numerous potential obesity-related risk loci in this cohort, including LGR4A750T. To broaden our research, we aim to leverage the extensive resources of the UK Biobank. We propose to analyze UK Biobank WES data for a more comprehensive examination of genetic variants associated with obesity, extending beyond LGR4A750T to other potential risk loci identified in our cohort. Moreover, we aim to investigate additional metabolic indicators, including blood pressure, lipid profiles, and glucose metabolism, to comprehensively understand the genetic determinants of obesity. Our objective is to construct a Chinese population-based genetic atlas that will enhance our understanding of obesity genetics.