Genetic Susceptibility Gene And Noninvasive Prenatal Diagnosis Study Of Psychiatric Disorders And Inherited Neurological Diseases

Exploration of genetic mechanism and molecular diagnosis method of inherited diseases are always important directions for genetic research.Being a category of complex diseases which influences brain functions,daily activities like cognition and behaviors,the morbidity of psychiatric disorders is co-affected by genetic and environmental factors.There have been several hypotheses for the pathogenesis of psychiatry,nonetheless we still do not have a definite conclusion.Inherited neurological disorders are also a major class of diseases that affect individual neurological functions,intelligence and behaviors,and can be divided into monogenic,polygenic,mitochondrial inherited and chromosomal diseases.For those with clear genetic mechanism,the molecular diagnosis methodology,especially for prenatal screening,has become a research territory in great demand.The perspective of glutamate hypothesis is that the dysfunction of glutamate NMDA receptor in brain is the pathogenic basis of schizophrenia.To investigate if the glutamate hypothesis related gene,NRGN and NRG1 are shared risk genes for schizophrenia,major depressive disorder and bipolar disorder in Han Chinese population,we performed genotyping of 20 tag SNPs of these two genes in 1248schizophrenia cases,1056 major depressive disorder cases,1344 bipolar disorder cases and 1248 normal controls,and analyzed their susceptibility.The association analysis results showed that rs4236710 and rs4512342 of NRG1 were associated with schizophrenia;Rs12278912 of NRGN and rs2919375 of NRG1 were associated with major depressive disorder;Rs7113041 of NRGN was associated with bipolar disorder.It was first reported that the haplotype bock of NRGN,rs7113041-rs12278912 was significantly associated with all three kinds of psychiatric disorders.The haplotype block,rs4512342-rs6982890 of NRG1 showed association with schizophrenia,while rs4531002-rs11989919 proved to be a shared risk haplotype for major depressive disorder and bipolar disorder（All results were adjusted by multiple test correction）.In the second part of this dissertation,we aimed at Down syndrome on behalf of inherited neurological diseases,and designed two noninvasive prenatal diagnosis methods based on maternal plasma cell free DNA detection.In the first strategy,we sequenced all plasma cfDNA of gravidas pregnant with normal or Down syndrome fetuses on ion torrent sequencing platform,and analyzed the proportion of chromosome 21 reads;In the second strategy,we firstly utilized the methylation difference of several sites between maternal and fetal tissues to enrich fetal cfDNA,then detected the copy number ratio of chromosome 21 to reference chromosome using TaqMan^TM probes on droplet digital PCR platform,and finally analyzed the positive detection rate using reference interval built with data of normal samples.Results indicated that T21 positive samples could be correctly distinguished from normal ones using ion torrent sequencing platform.Meanwhile,although the detection sensitivity of droplet digital PCR was currently lower than sequencing,it has already demonstrated its advantage and plasticity in prenatal screening compared to previous methods based on other quantitative PCR platforms.