DNA Pooling Base Genome-Wide Association Study Identifies Variants at NRXN3 Associated with Delayed Encephalopathy after Acute Carbon Monoxide Poisoning

Abstract

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is more characteristic of anoxic encephalopathy than of other types of anoxia. Those who have the same poisoning degree and are of similar age and gender have a greater risk of getting DEACMP. This has made it clear that there are obvious personal differences. Genetic factors may play a very important role. The authors performed a genome-wide association study involving pooling of DNA obtained from 175 patients and 244 matched acute carbon monoxide poisoning without delayed encephalopathy controls. The Illumina HumanHap 660 Chip array was used for DNA pools. Allele frequencies of all SNPs were compared between delayed encephalopathy after acute carbon monoxide poisoning and control groups and ranked. A total of 123 SNPs gave an OR >1.4. Of these, 46 mapped in or close to known genes. Forty-eight SNPs located in 19 genes were associated with DEACMP after correction for 5% FDR in the genome-wide association of pooled DNA. Two SNPs (rs11845632 and rs2196447) locate in the Neurexin 3 gene were selected for individual genotyping in all samples and another cohort consisted of 234 and 271 controls. There were significant differences in the genotype and allele frequencies of rs11845632 and rs2196447 between the DEACMP group and controls group (all P-values <0.05). This study describes a positive association between Neurexin 3 and controls in the Han Chinese population, and provides genetic evidence to support the susceptibility of DEACMP, which may be the resulting interaction of environmental and genetic factors.

Association between Neuron-Specific Enolase Gene Polymorphism and Delayed Encephalopathy after Acute Carbon Monoxide Poisoning

“…On this basis, some positive sites were, respectively, verified. The study confirmed that two SNPs (rs11845632, rs2196447) in axon protein 3 gene (NRXN3) correlated with DEACMP [ 18 ] and that there was a correlation between rs1784594 in the Parkin gene and DEACMP. We also found that allele A of rs1784594 may increase the risk of DEACMP in female ACMP patients [ 25 ], that LRP1B gene rs1541976 polymorphism is a potential susceptible factor of DEACMP [ 26 ], and that LRCH1 (rs1539177, rs17068697, rs9534475, and rs2236592) is associated with DEACMP [ 27 ].…”

“…It was suggested that individual differences that are determined by genetic factors may be involved in the occurrence of the disease and that the related genes and their polymorphic differences may play important roles. Our group used the Illumina 660W Quad whole-genome SNP genotyping chip to take the lead in completing the analysis of the whole genome SNP gene association (GWAS) of 175 DEACMP patients and 244 ACMP patients' peripheral blood samples in China and the group also screened the SNP sites that were related to DEACMP and identified 441 potential susceptible gene sites with a difference that was greater than 0.5 [ 18 ]. On this basis, some positive sites were, respectively, verified.…”

“…In recent years, Sequenom MassARRAY® has been proved to be an effective method for screening genetic susceptibility genes through SNP genotyping [ 17 ]. In the early stage of this study, an Illumina 660W Quad genome-wide SNP typing chip was used to complete the genome-wide SNP gene-wide association studies (GWAS) of peripheral blood samples of 175 DEACMP and 244 ACMP patients in China [ 18 ]. Allele frequencies of all SNPs were compared between delayed encephalopathy after ACMP and control groups and then ranked.…”

A fast and powerfulW-test for pairwise epistasis testing

“…Similar to the RTN4R, SLIT3 (SNP_A-2229791, MAF = 0.22, P -value = 3.7E−03) has been identified from copy-number variations analysis by whole genome sequencing ( 44 ) and mRNA expression studies ( 31 ). TMEM132D (SNP_A-8630842, MAF = 0.14, P -value = 5.9E−03) is found to associate with anxiety co-morbidity in depression and panic disorder by brain mRNA analysis ( 45 ); the NRXN3 (rs17108944, MAF = 0.03, P -value = 5.1E−3) has been reported to have a strong association with schizophrenia via studies of gene expression ( 46 ), DNA-pooling ( 47 ), and candidate genes.…”

A PARK2 polymorphism associated with delayed neuropsychological sequelae after carbon monoxide poisoning

“…Replicated associations were identified, and selected findings were confirmed by individual genotyping [13]. PARK2 was one of the promising genes (unpublished data).…”