Genetic Analyses Of Psychiatric Complex Traits Reveal The Role Of Pleiotry In Comobidy Of Psychiatric Disorders

Psychiatric disorders seriously affect human health and cause a significant socioenconomic burden.Psychiatric disorders such as depression,bipolar and schizophrenia are complex and heterogeneous.The current classification of psychiatric disorders reflects clinical syndromes with largely unknown etiology and is primarily based on historical descriptions provided by patients and clinicians.Many years of twin and family studies have shown that genetic fators contribute greatly to these syndromes.Through the estimation of heritability and genetic correlation between these psychiatric disorders,researchers are able to quantify the shared genetic etiology among these syndromes.In the era of genomics,genome-wide association study(GWAS)provides new opportunities to explore the mechanism of comorbidity underlying these disorders by assessing common genetic polymorphisms at several hundred thousand loci in the genome.Considered the cormibility among different psychiatric disorders is major research area in today human genetic studies,in this Ph D disseration,I explored two different areas related to genetic studies on complex traits,which are identification of susceptibility loci for a complex disorder and of shared genetic loci for two complex traits.(1)Detection of Significant Association Between Variants in Cannabinoid Receptor 1 Gene(CNR1)and Personality in African-American Population:Several studies have revealed significant associations between single nucleotide polymorphisms(SNPs)in the cannabinoid receptor 1(CNR1)gene and a broad spectrum of psychiatric disorders such as major depressive disorder(MDD),attention deficit hyperactivity disorder(ADHD),and schizophrenia.Personality traits that are highly related to susceptibility to these conditions have been associated with the CNR1 variants in subjects of Caucasian origin.However,there are no reported studies regarding the effects of CNR1 polymorphisms on personality traits in the African-American(AA)population.We performed an imputationbased association analysis for 26 CNR1 variants with five dimensions of personality in 3,046 AAs.SNPs rs806372 and rs2180619 showed a significant association with extraversion after Bonferroni correction for multiple testing(p < 0.0019).Further,several extraversionassociated SNPs were significantly associated with conscientiousness,agreeableness,and openness.SNP priority score analysis indicated that SNPs rs806368,rs806371,and rs2180619 play a role in the modulation of personality and psychiatric conditions.CNR1 is important in determining personality traits in the AA population.(2)Determination of shared genetic etiology and possible causal relations between tobacco smoking and depression:Cigarette smoking is highly associated with major depression disorder(MDD).However,genetic etiology of such comorbidity and causal relations is poorly understood,especially at the genome-wide level.In the present research,we analyzed summary data from genome-wide association study(GWAS)of the Psychiatric Genetic Consortium(PGC)for MDD(n = 191,005)and UK Biobank(UKBB)for smoking status(n = 337,030)and found significant genetic overlap between MDD and current/former smoking.By adopting a gene prioritization approach,we identified 43 genes shared by MDD and smoking,which were significantly enriched in the neurotransmitter system.We found a strong positive correlation between MDD and current smoking(rg = 0.365;p = 7.23e-25)and a negative correlation between MDD and former smoking(rg =-0.298;p = 1.59e-24).The Mendelian randomization(MR)analysis suggest that genetic liability for depression increase smoking.These findings inform the concomitant conditions of MDD and smoking and support the role of self-medication with smoking to counteract depression.In sum,although my thesis was separated into two parts,they are highly related to each other.In the first part,I showed the significant effects of CNR1 polymorphisms on personality traits in AAs and provided evidence supporting the presence of genetic correlation between personalities and mental health conditions.In the second part,I conducted a genome-wide overlap analysis for MDD and smoking using summary statistics from two large GWAS datasets.Such a systematic approach revealed the genetic correlation and causal relations between MDD and smoking,which present a comprehensive evaluation of shared genetic etiology.These findings will help to find disease-associated genetic variation and improve polygenic risk prediction as it makes its way into clinical practice.