22q 11.2 deletion syndrome（DS） is a complex developmental disorder with a high incidence of psychiatric illnesses,including schizophrenia and mood disorders.Recent studies have identified Guanine Nucleotide Binding ...22q 11.2 deletion syndrome（DS） is a complex developmental disorder with a high incidence of psychiatric illnesses,including schizophrenia and mood disorders.Recent studies have identified Guanine Nucleotide Binding Protein（G protein）Beta Polypeptide 1-Like（GNB1L）,located within the 1.5 Mbp 22q11.2 DS critical region,as a candidate liability gene for schizophrenia and bipolar disorder.In this study,we used mRNA expression measurements in Han Chinese postmortem temporal cortex and linkage disequilibrium（LD） analysis to show that GNB1 L is regulated by a cis-acting genetic variant within the 3＇-region of the gene.Significantly,this variant is located within an LD block that contains all of the common SNPs previously shown to associate with schizophrenia and bipolar disorder in Han Chinese and Caucasian populations.Contrary to our expectations,re-analysis of previously published case-control study data in light of our mRNA expression results implies that the GNB1 L highexpression allele is the risk allele for schizophrenia and bipolar disorder in the Han Chinese population.展开更多
Currently, there is great interest in identifying genetic variants that contribute to the risk of developing autism spectrum disor- ders （ASDs）, due in part to recent increases in the frequency of diagnosis of these...Currently, there is great interest in identifying genetic variants that contribute to the risk of developing autism spectrum disor- ders （ASDs）, due in part to recent increases in the frequency of diagnosis of these disorders worldwide. While there is nearly universal agreement that ASDs are complex diseases, with multiple genetic and environmental contributing factors, there is less agreement concerning the relative importance of common vs rare genetic variants in ASD liability. Recent observations that rare mutations and copy number variants （CNVs） are frequently associated with ASDs, combined with reduced fecundity of individuals with these disorders, has led to the hypothesis that ASDs are caused primarily by de novo or rare genetic muta- tions. Based on this model, large-scale whole-genome DNA sequencing has been proposed as the most appropriate method for discovering ASD liability genes. While this approach will undoubtedly identity many novel candidate genes and produce important new insights concerning the genetic causes of these disorders, a full accounting of the genetics of ASDs will be incomplete absent an understanding of the contributions of common regulatory variants, which are likely to influence ASD liability by modifying the effects of rare variants or, by assuming unfavorable combinations, directly produce these disorders. Because it is not yet possible to identify regulatory genetic variants by examination of DNA sequences alone, their identitication will require experimentation. In this essay, I discuss these issues and describe the advantages of measurements of allelic expression imbalance （AEI） of mRNA expression for identifying cis-acting regulatory variants that contribute to ASDs.展开更多
基金supported by the 985 Program of Ministry of Education,Chinathe National Basic Research Development Program(973 Program)of China(2009CB522007 and 2010CB529601)the National Natural Science Foundation of China(30870899 and 81070908)
文摘22q 11.2 deletion syndrome（DS） is a complex developmental disorder with a high incidence of psychiatric illnesses,including schizophrenia and mood disorders.Recent studies have identified Guanine Nucleotide Binding Protein（G protein）Beta Polypeptide 1-Like（GNB1L）,located within the 1.5 Mbp 22q11.2 DS critical region,as a candidate liability gene for schizophrenia and bipolar disorder.In this study,we used mRNA expression measurements in Han Chinese postmortem temporal cortex and linkage disequilibrium（LD） analysis to show that GNB1 L is regulated by a cis-acting genetic variant within the 3＇-region of the gene.Significantly,this variant is located within an LD block that contains all of the common SNPs previously shown to associate with schizophrenia and bipolar disorder in Han Chinese and Caucasian populations.Contrary to our expectations,re-analysis of previously published case-control study data in light of our mRNA expression results implies that the GNB1 L highexpression allele is the risk allele for schizophrenia and bipolar disorder in the Han Chinese population.
基金supported by the National Basic Research Program of China(Grant No.2010CB529600)the National Natural Science Foundation of China(Grant No.30870899)
文摘Currently, there is great interest in identifying genetic variants that contribute to the risk of developing autism spectrum disor- ders （ASDs）, due in part to recent increases in the frequency of diagnosis of these disorders worldwide. While there is nearly universal agreement that ASDs are complex diseases, with multiple genetic and environmental contributing factors, there is less agreement concerning the relative importance of common vs rare genetic variants in ASD liability. Recent observations that rare mutations and copy number variants （CNVs） are frequently associated with ASDs, combined with reduced fecundity of individuals with these disorders, has led to the hypothesis that ASDs are caused primarily by de novo or rare genetic muta- tions. Based on this model, large-scale whole-genome DNA sequencing has been proposed as the most appropriate method for discovering ASD liability genes. While this approach will undoubtedly identity many novel candidate genes and produce important new insights concerning the genetic causes of these disorders, a full accounting of the genetics of ASDs will be incomplete absent an understanding of the contributions of common regulatory variants, which are likely to influence ASD liability by modifying the effects of rare variants or, by assuming unfavorable combinations, directly produce these disorders. Because it is not yet possible to identify regulatory genetic variants by examination of DNA sequences alone, their identitication will require experimentation. In this essay, I discuss these issues and describe the advantages of measurements of allelic expression imbalance （AEI） of mRNA expression for identifying cis-acting regulatory variants that contribute to ASDs.
