A Study On Phenotype-wide Causal Association Of Obesity And Population Natural Selection Of Body Fat Distribution

The causal relationship between obesity and diseases needs to be further clarified.In addition,as an important indicator of obesity,there are differences in body fat distribution among different races,and the underlying genetic factors are unclear.Therefore,this study raises the following questions:1.Does obesity increase the risk of Myocardial Infarction Diabetic Retinopathy,and what are the unclear pathogenic pathways of obesity?What other health-related traits may have a causal relationship with obesity?2.What are the differences in body fat distribution and the natural selection-related genes that cause these differences in different populations?To answer the above two questions,this study used Mendelian randomization（MR）research methods,observational research methods,and natural selection signal detection methods to study the causal inference of obesity characterized by body mass index（BMI）and health-related phenotypes,population-specific body fat distribution characteristics,and natural selection genes related to body fat distribution.First,we use the"Two sample MR"method to conduct a two-stage causal inference analysis on samples from different data sources.The results that can be mutually verified in the two stages are taken as our causal inference conclusions.In addition to BMI,body fat distribution characteristics are also an important indicator for describing obesity.This study conducted an observational study on population-specific body fat distribution differences using Chinese populations（n=1,518）,African populations（n=7,702）,and European populations（n=460,537）from the UK Biobank database.Based on the differences in population-specific body fat distribution,natural selection research methods were applied to find genetic loci and genes related to body fat distribution.The research subjects of this part were East Asian,European and African population data from the 1000 Genomes Projects Consortium.The integrated haplotype score（i HS）,cross-population extended haplotype homozygosity（XP-EHH）,and fixation index(F_ST)methods were used to detect natural selection loci related to body fat distribution and screen for genetic loci and related genes of body fat distribution under natural selection.Our causal inference study shows that obesity increases Myocardial Infarction(OR=1.057,P-value=2.00×10^-3)and Diabetic Retinopathy(OR=1.016,P-value=2.53×10^-7)and found that obesity can lead to an increase in Red blood cell（RBC）count(Beta=0.012,P-value=7.9×10^-3),while the increase of RBC count could induced Type 2 Diabetes(OR=4.53,P-value=5.8×10^-5).This study also compared the body fat distribution characteristics of different populations in detail.Compared with Europeans and Africans,Chinese people have the lowest levels of height,weight,hip circumference,leg fat content,and overall fat content,but the waist-to-hip ratio is at the highest level,indicating that obesity in the Chinese population is more often manifested as abdominal obesity.Abdominal obesity may be influenced by eight alleles located in 14 genetic loci,including MAP2K5,SLBP,PITPNM2,MAP3K3,UQCC1,CEP250,COBLL1 and ZNF664.In summary,this study proposed its own views on the controversy over causal inference of obesity on Myocardial Infarction and Diabetic Retinopathy:supporting that obesity is a risk factor for Myocardial Infarction and Diabetic Retinopathy.This study also found that an increase in Red blood cell count may be an intermediate factor for obesity-induced Type 2Diabetes.On the other hand,this study found that the obesity characteristics of East Asians are mainly focused on abdominal obesity and natural selection-related genes participate in the genetic mechanism of this fat distribution characteristic.