Abstract Background : Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes. Results: In order to discover new susceptibility genes for HBV-related outcomes, we conducted a genome-wide association study in 1031 Chinese participants, including 275 HBV clearance subjects, 92 asymptomatic persistence infection carriers (ASPI), 93 chronic hepatitis B patients (CHB), 188 HBV-related decompensated cirrhosis patients (DC), 214 HBV-related hepatocellular carcinoma patients (HCC) and 169 healthy controls (HC). In the case-control study, we observed novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2 , P = 1.57×10 -6 ) and HCC (SNP: rs2833856, Gene: EVA1C , P = 1.62×10 -6 ; SNP: rs4661093, Gene: ETV3 , P = 2.26×10 -6 ). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1 , P = 1.85×10 -6 ), and three MHC loci ( HLA-DRB1, HLA-DPB1, HLA-DPA2 ) showed significant increased progressive risk from ASPI to CHB. Interestingly, underlying the evolutionary study of HBV-related genes in public database, we found that the derived allele of two HBV clearance related locus, rs3077 and rs9277542, are under strong selection in European population. Conclusions: In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Moreover, we identified two SNPs that show selective significance ( HLA-DPA1 , HLA-DPB1 ) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.
Abstract The neural tissue is rich in polyunsaturated fatty acids (PUFAs), components that are indispensable for the proper functioning of neurons, such as neurotransmission. PUFA nutritional deficiency and imbalance have been linked to a variety of chronic brain disorders, including major depressive disorder (MDD), anxiety, and anorexia. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. Here, we used genome-wide association summary statistics to systematically examine the shared genetic basis between six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917), infer their potential causal relationships, identify colocalized regions, and pinpoint shared genetic variants. Genetic correlation and polygenic overlap analyses revealed a widespread shared genetic basis for 77 trait pairs between six PUFA phenotypes and 16 brain disorders. Two-sample Mendelian randomization analysis indicated potential causal relationships for 16 pairs of PUFAs and brain disorders, including alcohol consumption, bipolar disorder (BIP), and MDD. Colocalization analysis identified 40 shared loci (13 unique) among six PUFAs and ten brain disorders. Twenty-two unique variants were statistically inferred as candidate shared causal variants, including rs1260326 ( GCKR ), rs174564 ( FADS2 ) and rs4818766 ( ADARB1 ). These findings reveal a widespread shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for the potential effects of PUFAs on certain brain disorders, especially MDD, BIP, and alcohol consumption.
Abstract Circulating polyunsaturated and monounsaturated fatty acid (PUFA and MUFA) levels, whose imbalances co-occur with human metabolic diseases, have strong heritable components. We performed the largest genome-wide association study (GWAS) to-date on fourteen PUFA and MUFA phenotypes, measured by nuclear magnetic resonance in plasma. We identified 612 significant locus-phenotype associations (115 unique loci; P < 1.678×10 -8 ) in a European cohort from UK Biobank (UKB-EUR; n=101,729). Replication of five phenotypes (omega-3, omega-6, DHA, LA, MUFAs) was conducted in two external European studies: FinMetSeq (n=8,751) and a meta-analysis by Kettunnen et al. (n=3,644-13,544). Meta-analysis of these three studies yielded 254 significant locus-phenotype associations (109 unique loci; P < 2.439×10 -8 ); we identified 87 novel loci, 51 of which were replicated. A transcriptome-wide association study of the UKB-EUR cohort revealed an additional twelve novel loci. This study improves our understanding of the genetic architecture of unsaturated fatty acids and can inform future genotype-based dietary interventions.
Abstract Background Dementia is a common disease influenced by both genetic and environmental factors. APOE ε4 is well-known to increase the risk of dementia, and it has been shown to attenuate the protective association of fish oil supplementation and the incidence of dementia. To identify more genetic factors with similar modifying effects, we performed a genome-wide scan. Methods We first performed time-to-event genome-wide association study (GWAS) of all-cause dementia and two of its subtypes, Alzheimer’s disease (AD) and vascular dementia, in the UK Biobank. GWAS were performed in all participants (N = 357,631) and in two subgroups with or without fish oil supplementation (N = 113,267 and 244,364, respectively). Single nucleotide polymorphisms (SNPs) suggestively associated with dementia were then evaluated for their interactions with fish oil status in Cox-regression models. Furthermore, we conducted gene set enrichment analysis to identify the relevant cell types for these interaction signals. Results Time-to-event GWAS identified 6, 5, and 2 genome-wide significant loci (p < 5e-8) for the incidence of all-cause dementia, AD, and vascular dementia, respectively. Most of them overlapped with previously known GWAS loci for AD and related dementia. A total of 178 suggestive GWAS loci (p < 1e-5) were passed onto interaction analysis, and 43 of them were found to significantly modify the association between fish oil supplementation and dementia incidence (p < 2.8e-4 with Bonferroni correction). One locus overlapped with a known AD GWAS locus ( EED / PICALM ) and two overlapped with GWAS loci for circulating omega-3 fatty acids ( SRSF4 , PSMG1 ). Gene set enrichment analysis found that candidate genes of interaction signals demonstrated tissue or cell-type specificity in the brain. Conclusion We identified 43 genetic loci that modify the association between fish oil supplementation and dementia. These findings indicate a need for genome-informed personalized nutrition of fish oil supplementation for the purpose of dementia prevention.
Abstract Background Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes. Methods Collected samples from different outcomes of HBV infection and performed genotyping by Affymetrix 500 k SNP Array. GCTA tool, PLINK, and Bonferroni method were applied for analysis of genotyping and disease progression. ANOVA was used to evaluate the significance of the association between biomarkers and genotypes in healthy controls. PoMo, F ST, Vcftools and Rehh package were used for building the racial tree and population analysis. F ST statistics accesses 0.15 was used as a threshold to detect the signature of selection. Results There are 1031 participants passed quality control from 1104 participants, including 275 HBV clearance, 92 asymptomatic persistence infection (ASPI), 93 chronic hepatitis B (CHB), 188 HBV-related decompensated cirrhosis (DC), 214 HBV-related hepatocellular carcinoma (HCC) and 169 healthy controls (HC). In the case–control study, one novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2 , P = 1.57 × 10 −6 ) and HCC (SNP: rs2833856, Gene: EVA1C , P = 1.62 × 10 −6 ; SNP: rs4661093, Gene: ETV3 , P = 2.26 × 10 −6 ). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1 , P = 1.85 × 10 −6 ), and three MHC loci ( HLA-DRB1, HLA-DPB1, HLA-DPA2 ) showed significant increased progressive risk from ASPI to CHB. Underlying the evolutionary study of HBV-related genes in public database, the derived allele of two HBV clearance related loci, rs3077 and rs9277542, are under strong selection in European population. Conclusions In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Two SNPs that show selective significance ( HLA-DPA1 , HLA-DPB1 ) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.
Previous genome-wide association studies (GWAS) have identified genetic loci associated with the circulating levels of FAs, but the biological mechanisms of these genetic associations remain largely unexplored. Here, we conducted GWAS to identify additional genetic loci for 19 circulating fatty acid (FA) traits in UK Biobank participants of European ancestry (N = 239,268) and five other ancestries (N = 508 - 4,663). We leveraged the GWAS findings to characterize genetic correlations and colocalized regions among FAs, explore sex differences, examine FA loci influenced by lipoprotein metabolism, and apply statistical fine-mapping to pinpoint putative causal variants. We integrated GWAS signals with multi-omics quantitative trait loci (QTL) to reveal intermediate molecular phenotypes mediating the associations between the genetic loci and FA levels. Altogether, we identified 215 significant loci for polyunsaturated fatty acids (PUFAs)-related traits in European participants, 163 loci for monounsaturated fatty acids (MUFAs)-related traits, and 119 loci for saturated fatty acids (SFAs)-related traits, including 70, 61, and 54 novel loci, respectively. A novel locus for total FAs, the percentage of omega-6 PUFAs in total FAs, and total MUFAs (around genes
Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in the loss of cognitive ability and memory. However, there is no specific treatment to mechanistically inhibit the progression of Alzheimer's disease, and most drugs only provide symptom relief and do not fundamentally reverse AD. Current studies show that triggering receptor expressed on myeloid cells 2 (TREM2) is predominantly expressed in microglia of the central nervous system (CNS) and is involved in microglia proliferation, survival, migration and phagocytosis. The current academic view suggests that TREM2 and its ligands have CNS protective effects in AD. Specifically, TREM2 acts by regulating the function of microglia and promoting the clearance of neuronal toxic substances and abnormal proteins by microglia. In addition, TREM2 is also involved in regulating inflammatory response and cell signaling pathways, affecting the immune response and regulatory role of microglia. Although the relationship between TREM2 and Alzheimer's disease has been extensively studied, its specific mechanism of action is not fully understood. The purpose of this review is to provide a comprehensive analysis of the research of TREM2, including its regulation of the inflammatory response, lipid metabolism and phagocytosis in microglia of CNS in AD, and to explore the potential application prospects as well as limitations of targeting TREM2 for the treatment of AD.
Objectives: We examined whether fish oil supplementation can modify the genetic potential for the circulating levels of four lipids, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Methods: A total of 441,985 participants with complete genetic and phenotypic data from the UK Biobank were included in our study. Polygenic scores (PGS) were calculated in participants of diverse ancestries. Multivariable linear regression models were used to assess associations with adjustment for relevant risk factors. Results: Fish oil supplementation mitigated genetic susceptibility to elevated levels of total cholesterol, LDL-C, and triglycerides, while amplifying genetic potential for increased HDL-C among 424,090 participants of European ancestry (Pinteraction < 0.05). For instance, in individuals taking fish oil supplements, each standard deviation (SD) increase in the PGS of triglycerides was associated with 0.254 (95% CI = 0.248 – 0.259) SD increase in the observed circulating level of triglycerides. In comparison, the association effect was 0.267 (95% CI = 0.263 – 0.270) in those not taking fish oil supplements. Consistent significant findings were obtained using PGS calculated based on multiple genome-wide association studies or alternative PGS methods. We also showed that fish oil significantly attenuated genetic predisposition to high triglycerides in African-ancestry participants. The association effect was 0.099 SD (95% CI = 0.070 – 0.128) in those with fish oil supplementation and 0.150 SD (95% CI = 0.125 – 0.174) in those without. Conclusions: Fish oil supplementation attenuated the genetic susceptibility to elevated blood levels of total cholesterol, LDL-C, and triglycerides, while accentuating genetic potential for higher HDL-C. These results suggest that fish oil may have a beneficial impact on modifying genome-wide genetic effects on elevated lipid levels in the general population. Funding Sources: This work was funded by the University of Georgia Research Foundation and by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R35GM143060.
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