TY - JOUR
T1 - Genome-Wide Epistatic Network Analyses of Semantic Fluency in Older Adults
AU - Tan, Qihua
AU - Li, Weilong
AU - Nygaard, Marianne
AU - An, Ping
AU - Feitosa, Mary
AU - Wojczynski, Mary K.
AU - Zmuda, Joseph
AU - Arbeev, Konstantin
AU - Ukraintseva, Svetlana
AU - Yashin, Anatoliy
AU - Christensen, Kaare
AU - Mengel-From, Jonas
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/5
Y1 - 2024/5
N2 - Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10−8; rs880179, p = 4.83 × 10−8) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10−5 < p < 7.35 × 10−3), of which two were replicated (p < 3.10 × 10−3). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.
AB - Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10−8; rs880179, p = 4.83 × 10−8) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10−5 < p < 7.35 × 10−3), of which two were replicated (p < 3.10 × 10−3). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.
KW - GWAS
KW - LLFS
KW - elderly
KW - epistasis
KW - semantic fluency
UR - http://www.scopus.com/inward/record.url?scp=85194219640&partnerID=8YFLogxK
U2 - 10.3390/ijms25105257
DO - 10.3390/ijms25105257
M3 - Article
C2 - 38791296
AN - SCOPUS:85194219640
SN - 1661-6596
VL - 25
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 10
M1 - 5257
ER -