Jihye Ryu

Genome-wide association study reveals five nucleotide sequence variants for carcass traits in beef cattle

Genetic associations of nucleotide sequence variants with carcass traits in beef cattle were investigated using a genome-wide single nucleotide polymorphism (SNP) assay. Three hundred and thirteen Korean cattle were genotyped with the Illumina BovineSNP50 BeadChip, and 39,129 SNPs from 311 animals were analysed for each carcass phenotype after filtering by quality assurance. Five sequence markers were associated with one of the meat quantity or quality traits; rs109593638 on chromosome 3 with marbling score, rs109821175 on chromosome 11 and rs110862496 on chromosome 13 with backfat thickness (BFT), and rs110228023 on chromosome 6 and rs110201414 on chromosome 16 with eye muscle area (EMA) (P < 1.27 × 10(-6) , Bonferonni P < 0.05). The ss96319521 SNP, located within a gene with functions of muscle development, dishevelled homolog 1 (DVL1), would be a desirable candidate marker. Individuals with genotype CC at this gene appeared to have increased both EMA and carcass weight. Fine-mapping would be required to refine each of the five association signals shown in the current study for future application in marker-assisted selection for genetic improvement of beef quality and quantity.

Association of glycosylated hemoglobin with the gene encoding CDKAL1 in the Korean Association Resource (KARE) study.

Genome‐wide associations with glycosylated hemoglobin, which reflects the long‐term glycemia, were examined using two independent cohorts of the Korea Association Resource (KARE) consortium. We first identified sequence variants within a linkage disequilibrium block (r2 > 0.98) in the intron 5 of cyclin‐dependent kinase 5 regulatory subunit‐associated protein 1‐like 1 (CDKAL1) gene using 4,275 normoglycemic subjects of Cohort 1 (P < 2.5 × 10−8). The association was replicated in 3,782 normoglycemic subjects of Cohort 2. Furthermore, the sequence variants were also associated with glucose levels after oral glucose tolerance test. Especially, a strong association with 1 h glucose (P = 1.3 × 10−11) led us to interpreting that CDKAL1 might influence the level of glycosylated hemoglobin by affecting 1 h glucose level. Ultimately, accumulated effects on the glycosylated hemoglobin level by the genetic variation of CDKAL1 might affect susceptibility to type 2 diabetes mellitus. Hum Mutat 33:655–659, 2012.

Genetic dissection of susceptibility to vascular dementia.

Vascular dementia (VD) is the dementia induced by cerebrovascular lesions with a variety of pathophysiological subtypes. Our knowledge of the genetic mechanism of VD was restricted to a few Mendelian forms of VD. The complexity of sporadic VD caused by individual and interactive genetic effects under various environmental exposures renders it difficult to uncover genetic determinants. Much more effort has been made to identify associations of various candidate genes and to explain the variability of the complex VD than the Mendelian VD. The identified genes, however, explain a small portion of the heritability of VD, and the associations are often controversial in different populations. This makes understanding the genetic architecture of VD more complicated. We studied the genes and their sequence variants associated with susceptibility to VD, and many of the genes were involved in lipid metabolism, angiotensin, and inflammation. We also discussed future directions for the association analysis. Endeavors with various approaches would eventually show the genetic architecture of VD and provide a valuable tool in stratifying patients according to their genotypes. This is the first review to introduce a variety of primary studies that may offer some foundation for the genetics of VD.

Identification of contemporary selection signatures using composite log likelihood and their associations with marbling score in Korean cattle.

Positive selection not only increases beneficial allele frequency but also causes augmentation of allele frequencies of sequence variants in close proximity. Signals for positive selection were detected by the statistical differences in subsequent allele frequencies. To identify selection signatures in Korean cattle, we applied a composite log-likelihood (CLL)-based method, which calculates a composite likelihood of the allelic frequencies observed across sliding windows of five adjacent loci and compares the value with the critical statistic estimated by 50,000 permutations. Data for a total of 11,799 nucleotide polymorphisms were used with 71 Korean cattle and 209 foreign beef cattle. As a result, 147 signals were identified for Korean cattle based on CLL estimates (P < 0.01). The signals might be candidate genetic factors for meat quality by which the Korean cattle have been selected. Further genetic association analysis with 41 intragenic variants in the selection signatures with the greatest CLL for each chromosome revealed that marbling score was associated with five variants. Intensive association studies with all the selection signatures identified in this study are required to exclude signals associated with other phenotypes or signals falsely detected and thus to identify genetic markers for meat quality.

Profile of differential promoter activity by nucleotide substitution at GWAS signals for multiple sclerosis.

AbstractThis experimental study was conducted with completely randomized design.Genome-wide association studies (GWAS) have revealed a large number of genetic associations of nucleotide sequence variants with susceptibility to multiple sclerosis (MS). Nevertheless, studies to identify the functional relevance of these variants lag far behind identification of the GWAS signals. Expression quantitative trait loci (eQTLs) analysis and promoter activity analysis with the variants filtered by GWAS were conducted to identify their functional alleles and haplotypes. The promoter activity was assayed with reporter constructs containing variants at 8 MS GWAS signals resulted from 18 GWAS.The promoter activity differed by alternative sequence variants at upstream regions of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes (P < 0.05). The transcriptional regulations of sequence variants were also found by identifications of eQTLs for their corresponding genes with lymphoblastoid cells in the current study (SYK, ODF3B, RGS14, and PVR, P < 8.33 × 10−3) and with dendritic cells in a previous study (CYP27B1, P = 1.84 × 10−6).This study identified regulatory nucleotide sequences in the promoters of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes, and their variants differentially affected gene expression. This might result in their associations with MS susceptibility in previous GWAS. Further functional studies are required to understand the process of transcriptional regulation of the variants identified in the current study and the mechanisms underlying susceptibility to MS.

Strong cis-acting expression quantitative trait loci for the genes encoding SNHG5 and PEX6.

AbstractExpression of quantitative trait loci (eQTLs) for the genes located in human chromosome 6 were examined. Data on RNA expression in lymphoblastoid cells of 373 unrelated Europeans were used to identify eQTLs.Genome-wide analysis resulted in 24,447 nucleotide variants associated with gene expression (P < 2.16 × 10−10). We found 36variants with P < 10−100, which were all associated with expression levels of the genes encoding small nucleolar RNA host gene 5 (SNHG5) and peroxisomal biogenesis factor 6 (PEX6). Enhancer eQTLs downstream of theSNHG5 gene might be candidate genetic factors for susceptibility to cancer. This is because nucleotide substitutions (eg, G→T at rs6922) of the enhancer eQTLs may cause low expression of SNHG5 gene, and low expression of snoRNA U50, a product generated from introns of the SNHG5gene, can induce cancer. One presently identified eQTL for the PEX6 gene was rs10948059, which had been associated with prostate cancer from previous association studies. The results imply that variants associated with prostate cancer can be identified through expressional change in the PEX6 gene, but not in the overlapped glycine N-methyltransferase gene which had been considered as a candidate gene.Further studies are required to understand their underlying mechanisms for the strong eQTLs for the SNHG5 and PEX6 genes.

Genome-wide association study reveals sex-specific selection signals against autosomal nucleotide variants

A genome-wide association study (GWAS) was conducted to examine genetic associations of common autosomal nucleotide variants with sex in a Korean population with 4183 males and 4659 females. Nine genetic association signals were identified in four intragenic and five intergenic regions (P<5 × 10−8). Further analysis with an independent data set confirmed two intragenic association signals in the genes encoding protein phosphatase 1, regulatory subunit 12B (PPP1R12B, intron 12, rs1819043) and dynein, axonemal, heavy chain 11 (DNAH11, intron 61, rs10255013), which are directly involved in the reproductive system. This study revealed autosomal genetic variants associated with sex ratio by GWAS for the first time. This implies that genetic variants in proximity to the association signals may influence sex-specific selection and contribute to sex ratio variation. Further studies are required to reveal the mechanisms underlying sex-specific selection.

Genome-wide identification of expression quantitative trait loci for human telomerase.

AbstractA genome-wide association study was conducted to identify expression quantitative trait loci (eQTL) for human telomerase.We tested the genetic associations of nucleotide variants with expression of the genes encoding human telomerase reverse transcriptase (hTERT) and telomerase RNA components (TERC) in lymphoblastoid cell lines derived from 373 Europeans.Our results revealed 6 eQTLs associated with hTERT (P < 5 × 10–8). One eQTL (rs17755753) was located in the intron 1 of the gene encoding R-spondin-3 (RSPO3), a well-known Wnt signaling regulator. Transcriptome-wide association analysis for these eQTLs revealed their additional associations with the expression of 29 genes (P < 4.75 × 10–6), including prickle planar cell polarity protein 2 (PRICKLE2) gene important for the Wnt signaling pathway. This concurs with previous studies in which significant expressional relationships between hTERT and some genes (&bgr;-catenin and Wnt-3a) in the Wnt signaling pathway have been observed.This study suggested 6 novel eQTLs for hTERT and the association of hTERT with the Wnt signaling pathway. Further studies are needed to understand their underlying mechanisms to improve our understanding of the role of hTERT in cancer.

Differential promoter activity by nucleotide substitution at a type 2 diabetes genome‐wide association study signal upstream of the wolframin gene

Functional knowledge of most genetic variants identified from genome‐wide association studies (GWAS) for type 2 diabetes (T2D) is limited. A recent T2D GWAS revealed an association signal (rs4689388) upstream of the gene encoding Wolfram syndrome 1 (WFS1) whose intrinsic nucleotide variants had been previously associated with T2D in several candidate gene analyses. The aim of the present study was to identify functional variants of the GWAS signal.

Genetic association of marbling score with intragenic nucleotide variants at selection signals of the bovine genome

Selection signals of Korean cattle might be attributed largely to artificial selection for meat quality. Rapidly increased intragenic markers of newly annotated genes in the bovine genome would help overcome limited findings of genetic markers associated with meat quality at the selection signals in a previous study. The present study examined genetic associations of marbling score (MS) with intragenic nucleotide variants at selection signals of Korean cattle. A total of 39 092 nucleotide variants of 407 Korean cattle were utilized in the association analysis. A total of 129 variants were selected within newly annotated genes in the bovine genome. Their genetic associations were analyzed using the mixed model with random polygenic effects based on identical-by-state genetic relationships among animals in order to control for spurious associations produced by population structure. Genetic associations of MS were found (P<3.88×10-4) with six intragenic nucleotide variants on bovine autosomes 3 (cache domain containing 1, CACHD1), 5 (like-glycosyltransferase, LARGE), 16 (cell division cycle 42 binding protein kinase alpha, CDC42BPA) and 21 (snurportin 1, SNUPN; protein tyrosine phosphatase, non-receptor type 9, PTPN9; chondroitin sulfate proteoglycan 4, CSPG4). In particular, the genetic associations with CDC42BPA and LARGE were confirmed using an independent data set of Korean cattle. The results implied that allele frequencies of functional variants and their proximity variants have been augmented by directional selection for greater MS and remain selection signals in the bovine genome. Further studies of fine mapping would be useful to incorporate favorable alleles in marker-assisted selection for MS of Korean cattle.