Bivariate Genome-wide Association Study Of Cognitive Performance And Hearing Phenotypes

Objective:Age-related hearing loss and cognitive decline which are caused by multiple genetic and environmental factors are public health challenges in the world.Studies have shown that hearing loss and cognitive decline have a common pathogenesis and genetic basis,and few studies have focused on the bivariate association between hearing loss and cognitive function.Therefore,bivariate structural equation models and genome-wide association studies（GWAS）of cognition-BEHL_0.5,cognition-BEHL₁,cognition-BEHL₂,cognition-BEHL₄,cognition-BEHL₈,cognition-PTA₃ and cognition-PTA₂,were performed to explore the single nucleotide polymorphisms（SNPs）,genes and pathways in this study.Methods:The participants were recruited from Qingdao twin registry system.We used Mx software to compose bivariate Cholesky decomposition model and then access the genetic and environmental effects on phenotypic correlation.DNA samples of 131dizygotic twin pairs were genotyped using the Illumina’s Infnium Omni2.5Exome-8v1.2Bead Chip-platform（Illumina,San Diego,California,USA）.IMPUTE2 software was used to impute un-typed SNPs.Genome-wide efficient mixed model analysis（GEMMA）was performed in SNPs based analysis.In addition,gene-based analysis and enrichment analysis were performed by VEGAS2（Versatile Gene-based Association Study-2）and PASCAL,respectively.Results:A total of 359 twin pairs,including 131 dizygotic pairs were included.The mean age of participants was 51.6±7.6 years.（1）Bivariate genetic correlations of cognition-BEHL_0.5,cognition-BEHL₁,cognition-BEHL₂,cognition-BEHL₄,cognition-BEHL₈,cognition-PTA₃ and cognition-PTA₂ were-0.46、-0.42、-0.45、-0.46、-0.44、-0.55 and-0.48,after adjusting age and sex.（2）In the SNP-based analysis,we nominated 48,48,38,34,43,54,and 42 SNPs exceeding suggestive significance(P<1×10^-5)in analysis of cognition-BEHL_0.5,cognition-BEHL1,cognition-BEHL2,cognition-BEHL4,cognition-BEHL8,cognition-PTA₃ and cognition-PTA₂.The related SNPs with cognition-BEHL_0.5,cognition-BEHL1,cognition-BEHL2,cognition-BEHL4,cognition-BEHL8,cognition-PTA₃ and cognition-PTA₂were rs17134675,near in SDK1(P=5.02×10^-8);22:43742432 near EFCAB6(P=1.61×10^-7);rs4948351 locating in SLC16A9(P=8.25×10^-8);rs35728067 locating in FAM169B(P=7.07×10^-6);rs2096982 locating in PRKN(P=2.71×10^-7);rs16910593 locating in MICAL2(P=6.79×10^-8);and rs4395499near LDB2(P=5.09×10^-8).After performing imputing analysis,we nominated 157,457,193,312,248,218 and 340 SNPs exceeding suggestive significance(P<1×10^-5),respectively.（3）In the analysis of gene,we nominated one gene exceedingly statistically significant(P<5×10^-8)which was related to cognition-BEHL₂.Besides,we found that 1000,1038,1106,1048,1083,1049 and 1024 genes were related to cognition-BEHL_0.5,cognition-BEHL₁,cognition-BEHL₂,cognition-BEHL₄,cognition-BEHL₈,cognition-PTA₃ and cognition-PTA₂,respectively（P<0.05）.C20orf196,WDPCP,SLC16A9,TEX26,TEX26,WDPCP and TEX26 were related to cognition-BEHL_0.5,cognition-BEHL₁,cognition-BEHL₂,cognition-BEHL₄,cognition-BEHL₈,cognition-PTA₃ and cognition-PTA₂ with smallest P value,respectively.（4）In the pathway analysis,680,892,781,685,780,803 and 721 pathways were found significantly associated with cognition-BEHL_0.5,cognition-BEHL₁,cognition-BEHL₂,cognition-BEHL₄,cognition-BEHL₈,cognition-PTA₃ and cognition-PTA₂,respectively（P<0.05）.The pathways associated with cognition-BEHL_0.5,cognition-BEHL₁,cognition-BEHL₂,cognition-BEHL₄,cognition-BEHL₈,cognition-PTA₃ and cognition-PTA₂ were regulation of MRAN stability by proteins that bind au rich elements,metabolism of proteins,activation of the pre-replicative complex,signaling by FGFR in disease,DAG and IP3 signaling,mitotic G1 G1 S phases and signaling by FGFR in disease.Conclusion:We found the moderate bivariate genetic correlations of hearing and cognitive performance,and found some SNPs,genes and pathways were associated with hearing and cognitive performance.