Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) (∼360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region. Specifically, rs6426749-G allele can bind transcription factor TFAP2A, which efficiently elevates the enhancer activity and increases LINC00339 expression. Downregulation of LINC00339 significantly increases the expression of CDC42 in osteoblast cells, which is a pivotal regulator involved in bone metabolism. Our study provides mechanistic insight into how a noncoding SNP affects osteoporosis by long-range interaction, a finding that could indicate promising therapeutic targets for osteoporosis.
Background Childhood obesity is reported to be associated with the risk of many diseases in adulthood. However, observational studies cannot fully account for confounding factors. We aimed to systematically assess the causal associations between childhood body mass index (BMI) and various adult traits/diseases using two-sample Mendelian randomization (MR). Methods After data filtering, 263 adult traits genetically correlated with childhood BMI (P < 0.05) were subjected to MR analyses. Inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods were used to estimate the causal effects. Multivariable MR analysis was performed to test whether the effects of childhood BMI on adult traits are independent from adult BMI. Results We identified potential causal effects of childhood obesity on 60 adult traits (27 disease-related traits, 27 lifestyle factors, and 6 other traits). Higher childhood BMI was associated with a reduced overall health rating (β = − 0.10, 95% CI − 0.13 to − 0.07, P = 6.26 × 10−11). Specifically, higher childhood BMI was associated with increased odds of coronary artery disease (OR = 1.09, 95% CI 1.06 to 1.11, P = 4.28 × 10−11), essential hypertension (OR = 1.12, 95% CI 1.08 to 1.16, P = 1.27 × 10−11), type 2 diabetes (OR = 1.36, 95% CI 1.30 to 1.43, P = 1.57 × 10−34), and arthrosis (OR = 1.09, 95% CI 1.06 to 1.12, P = 8.80 × 10−9). However, after accounting for adult BMI, the detrimental effects of childhood BMI on disease-related traits were no longer present (P > 0.05). For dietary habits, different from conventional understanding, we found that higher childhood BMI was associated with low calorie density food intake. However, this association might be specific to the UK Biobank population. Conclusions In summary, we provided a phenome-wide view of the effects of childhood BMI on adult traits. Multivariable MR analysis suggested that the associations between childhood BMI and increased risks of diseases in adulthood are likely attributed to individuals remaining obese in later life. Therefore, ensuring that childhood obesity does not persist into later life might be useful for reducing the detrimental effects of childhood obesity on adult diseases.
BackgroundTriple-negative breast cancer (TNBC) is a particular breast cancer subtype with poor prognosis due to its aggressive biological behavior and lack of targets for therapy. This study aimed to explore the expression profile and potential function of lncRNAs in TNBC through bioinformatic methods.MethodsTwo microarrays of TNBC were obtained from the Gene Expression Omnibus database. Differentially expressed lncRNAs and mRNAs were screened out and the expressions of top lncRNAs and overlapping lncRNAs were validated using data from The Cancer Genome Atlas database. The co-expression analysis of lncRNAs and mRNAs was conducted using R software and functional enrichment analysis for was performed by Metascape. Kaplan–Meier Plotter was used for survival analysis.ResultsA total of 1034 dysregulated lncRNAs were found in the two microarrays, and there were 8 overlapped lncRNAs. Among them, 537 lncRNAs were significantly correlated with 451 protein-coding genes (PCGs). The co-expressed PCGs were mainly enriched in terms including cell division, cell cycle, and protein/DNA binding, and were involved in pathways in cancer and other pathways such as PI3K-Akt, MAPK, ErbB and p53 signaling pathways. Hub-genes in the co-expression network were identified, and 7 of them were associated with relapse-free survival of TNBC (MAGI2-AS3: HR = 0.51; GGTA1P: HR = 0.54; NAP1L2: HR = 0.59; CRABP2: HR = 0.41; SYNPO2: HR = 0.50; MKI67: HR = 2.23; COL4A6: HR = 1.91; all P < 0.05).ConclusionsNumerous lncRNAs were dysregulated in TNBC, and many of them are possibly involved in cancer biology. Several of these lncRNAs were associated with of TNBC prognosis, which can be promising biomarkers.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0598-8) contains supplementary material, which is available to authorized users.
Taking together from both physiological and genetic levels, we suggest that FGF21 is inversely associated with regional BMD. And we haven't observed sex-specific effect in this study.
We aimed to summarize the results of genetic association studies for obesity and provide a comprehensive annotation of all susceptibility single nucleotide polymorphisms (SNPs). A total of 72 studies were summarized, resulting in 90,361 susceptibility SNPs (738 index SNPs and 89,623 linkage disequilibrium SNPs). Over 90% of the susceptibility SNPs are located in non-coding regions, and it is challenging to understand their functional significance. Therefore, we annotated these SNPs by using various functional databases. We identified 24,623 functional SNPs, including 4 nonsense SNPs, 479 missense SNPs, 399 untranslated region SNPs which might affect microRNA binding, 262 promoter and 5,492 enhancer SNPs which might affect transcription factor binding, 7 splicing sites, 76 SNPs which might affect gene methylation levels, 1,839 SNPs under natural selection and 17,351 SNPs which might modify histone binding. Expression quantitative trait loci analyses for functional SNPs identified 98 target genes, including 69 protein coding genes, 27 long non-coding RNAs and 3 processed transcripts. The percentage of protein coding genes that could be correlated with obesity-related pathways directly or through gene-gene interaction is 75.36 (52/69). Our results may serve as an encyclopaedia of obesity susceptibility SNPs and offer guide for functional experiments.
Obesity is highly heritable, but the specific genes influencing obesity related traits are largely unknown. Fibroblast growth factor 2 (FGF2) could influence adipocyte differentiation. However, the association of FGF2 polymorphisms and obesity remains unclear. This study aimed to investigate the associations of both the plasma FGF2 levels and SNPs in FGF2 gene with obesity phenotypes in Han Chinese populations. Plasma FGF2 levels were measured and subjected to association analyses in 62 subjects. Eleven SNPs in FGF2 were genotyped and tested for associations in a discovery sample of 1,300 subjects. SNPs significantly associated with obesity were subjected to replication in another independent sample of 1,035 subjects. We found that plasma FGF2 levels were positively correlated with fat mass (P = 0.010). Association analyses in the discovery sample identified three SNPs (rs1449683, rs167428, rs308442) significantly associated with fat mass after multiple testing adjustments (P < 0.0045). Subsequent replication study successfully validated one SNP (rs167428) associated with fat mass (Pcombine = 3.46 × 10−5). eQTL analyses revealed that SNPs associated with obesity also affected FGF2 expression. Our findings suggested that high plasma FGF2 level correlated with increased risk of obesity, and FGF2 gene polymorphisms could affect individual variances of obesity in Han Chinese population.
Nearly 95% of susceptibility SNPs identified by genome-wide association studies (GWASs) are located in non-coding regions, which causes a lot of difficulty in deciphering their biological functions on disease pathogenesis. Here, we aimed to conduct a comprehensive functional annotation for all the schizophrenia susceptibility loci obtained from GWASs. Considering varieties of epigenomic regulatory elements, we annotated all 22,688 acquired susceptibility SNPs according to their genomic positions to obtain functional SNPs. The comprehensive annotation indicated that these functional SNPs are broadly involved in diverse biological processes. Histone modification enrichment showed that H3K27ac, H3K36me3, H3K4me1, and H3K4me3 were related to the development of schizophrenia. Transcription factors (TFs) prediction, methylation quantitative trait loci (meQTL) analyses, expression quantitative trait loci (eQTL) analyses, and proteomic quantitative trait loci analyses (pQTL) identified 447 target protein-coding genes. Subsequently, differential expression analyses between schizophrenia cases and controls, nervous system phenotypes from mouse models, and protein–protein interaction with known schizophrenia-related pathways and genes were carried out with our target genes. We finaly prioritized 10 target genes for schizophrenia (CACNA1C, CLU, CSNK2B, GABBR1, GRIN2A, MAPK3, NOTCH4, SRR, TNF, and SYNGAP1). Our results may serve as an encyclopedia of schizophrenia susceptibility SNPs and offer holistic guides for post-GWAS functional experiments.
Previous studies have identified FGF2 as a susceptibility gene for osteoporosis in Caucasians. Evaluating the genetic associations in different ethnicities is necessary. Moreover, elucidating the functional mechanism for the susceptibility loci is important to offer new targets for therapeutic studies. Here, we genotyped 10 SNPs in FGF2 and tested for associations with bone mineral density (BMD) in a discovery sample of 1,300 Chinese subjects. Nominally significant results were subjected to replication in another sample of 1,039 Chinese subjects. We identified one SNP rs1048201:C>T in FGF2 3'untranslated region significantly associated with spine BMD (combined cohorts, P = 1.53×10 ). Expression quantitative trait locus analyses revealed that rs1048201 also affected FGF2 gene expression (P = 7.03×10 ). Bioinformatics prediction suggested that rs1048201 T allele could disrupt miRNA binding. Luciferase assay validated that the C allele had a repressive effect on FGF2 gene expression. We found that hsa-miR-196a-3p affected expression on both mRNA and protein levels of FGF2. In conclusion, our study provided evidence that a functional SNP rs1048201 was associated with BMD, and SNP rs1048201:C>T variant may act by affecting binding of hsa-miR-196a-3p. The SNP-modified posttranscriptional gene regulation by miRNA could be a potentially pathogenetic mechanism of osteoporosis.
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