Heritability And Genome-wide Association Study Of Depression In Adult Twins

Background:Depression is a common mental illness with an increasing incidence in recent years.Environmental factors and genetic factors have a certain degree of influence on the onset of depression.However,there are only few studies have explored the genome-wide association study（GWAS）of depression in China.Therefore,the purpose of this study is to explore the influence of genetic factors on depression in twin populations in Qingdao,as well as depression-related single nucleotide polymorphisms（SNPs）,genes and pathways.Methods:The participants of this study were selected from the adult twins of the twin registration system of Qingdao.The score of depressive symptoms was assessed by GDS-30 scale.The zygosity of twin was gradually identified by the gender,ABO blood type,and microsatellite DNA gene scanning and typing technology.The Mx software package was used to construct a structural equation model,and the heritability of depression was estimated according to the best fit model.The Infinium Omni2.5 Exome-8V1.2 Bead Chip chip was used for genotyping,and IMPUTE2 software was used to impute the untyped SNPs.In GWAS,the Genome-wide Efficient Mixed Model Association（GEMMA）was used for SNPs-based analysis,and the Manhattan plot was used to show the SNPs associated with depression.In addition,VEGAS2（Versatile Gene-Based Association Study-2）was used for gene-based analysis,and PASCAL（Pathway enrichment analysis）was used for pathway-based analysis.In addition,expression quantitative trait locus（eQTL）analysis was conducted to explore the cis-eQTL in brain,thyroid,tibial nerve and whole blood.Results:A total of 382 pairs of twins were included in this study,including 243 pairs of monozygotic（MZ）twins and 139 pairs of dizygotic（DZ）twins.382 pairs of twins were used for heritability analysis,and 139 pairs of DZ twins were used for GWAS analysis.The subjects ranged in age from 33 to 80,the median was 50 years old and the interquartile was12 years old.The score of depression ranged from 0-27 points,and the median and interquartile range were both 7.In the heritability analysis,the correlation of MZ twins（rMZ=0.43）was less than twice that of DZ twins（r DZ=0.25）,so the ACE model was chosen.Then through the likelihood ratio chi-square test,the simplest principle and Akaike’s information criterion,the AE model was determined to be the optimal model.The heritability of depression was 43.79%（95%CI:33.87%-52.65%）.A total of 1,339,089 qualified SNPs sites were used for GWAS analysis in this study.In the SNPs-based analysis,theQ-Q plot indicated that there was no possible population stratification phenomenon.The Manhattan chart showed that there were no SNPs that exceed the significance level(P<5×10^-8),but 15 SNPs were found to exceed the recommended association level(P<1×10^-5),including rs10851768,rs4776862 rs55795943,rs9260936 and rs2861190 etc.After imputation of untyped SNPs,we still didn’t find any SNPs that exceeded the significant level,but we found 56 SNPs that exceeded the recommended association level,13 of which were duplicated before imputation.In a gene-based analysis,1034 genes were found to be associated with depression P<0.05),including TMEM257,SCNN1B and OR6N1,etc.In pathway-based analysis,626 biological pathways were found to be associated with depression,including systemic lupus erythematosus,nicotinate and nicotinamide metabolism,activation of chaperon genes by Xbp-1s and so on.Though eQTL analysis,we found that 17 SNPs were the significant eQTLs in at least one relevant tissue（brain,thyroid,tibial nerve and whole blood）.We also identified that 13 of the top 20 genes harbored statistically significant cis-eQTLs in at least one relevant tissue.Conclusions:This study indicates that depression is inherited at a moderate level in twins in Qingdao city.Meanwhile,this study also found some depression-related SNPs loci,genes and biological pathways,which provide a relevant basis for future molecular biology research of depression.