Association Analysis Of Single Nucleotide Polymorphisms Research Articles

Genetic insights into hypoxia tolerance in silver sillago (Sillago sihama) through QTL mapping and SNP association analysis

Oxygen is vital for the survival, growth, development, and reproduction of organisms. This study investigates the genetic basis of hypoxia tolerance in the silver sillago (Sillago sihama), a species highly valued in aquaculture despite its traditional susceptibility to low oxygen environments. By employing quantitative trait locus (QTL) mapping and single nucleotide polymorphism (SNP) association studies, the study enhances our comprehension of the genetic factors involved in hypoxia tolerance. Six QTLs associated with hypoxia tolerance have been identified, spanning five distinct linkage groups. Enrichment analyses highlighted important biological processes and pathways, particularly those related to potassium ion transport and cytochrome P450-mediated drug metabolism, which play a critical role in responding to hypoxia stress. Seven candidate genes have been identified as relevant to hypoxia tolerance: cyp20a1, mgst3b, kcnh2, cluh, adk, xdh, and slc19a2. Notably, the SNP association analysis has identified 13 SNPs within the mgst3b gene, with five SNPs (g.583 T > C, g.611 A > G, g.629 T > A, g.633 T > A, g.937 A > G) showing a significant association with hypoxia tolerance. This study sheds light on the molecular mechanisms underlying hypoxia tolerance and suggests potential genetic markers that could be used to enhance S. sihama's ability to withstand hypoxic conditions through selective breeding, providing valuable insights for the improvement of sustainable aquaculture practices.

Genome-wide meta-analysis of short-tandem repeats for Parkinson's disease risk using genotype imputation.

Idiopathic Parkinson's disease is determined by a combination of genetic and environmental factors. Recently, the first genome-wide association study on short-tandem repeats in Parkinson's disease reported on eight suggestive short-tandem repeat-based risk loci (α = 5.3 × 10-6), of which four were novel, i.e. they had not been implicated in Parkinson's disease risk by genome-wide association analyses of single-nucleotide polymorphisms before. Here, we tested these eight candidate short-tandem repeats in a large, independent Parkinson's disease case-control dataset (n = 4757). Furthermore, we combined the results from both studies by meta-analysis resulting in the largest Parkinson's disease genome-wide association study of short-tandem repeats to date (n = 43 844). Lastly, we investigated whether leading short-tandem repeat risk variants exert functional effects on gene expression regulation based on methylation quantitative trait locus data in human 'post-mortem' brain (n = 142). None of the eight previously reported short-tandem repeats were significantly associated with Parkinson's disease in our independent dataset after multiple testing correction (α = 6.25 × 10-3). However, we observed modest support for short-tandem repeats near CCAR2 and NCOR1 in the updated meta-analyses of all available data. While the genome-wide meta-analysis did not reveal additional study-wide significant (α = 6.3 × 10-7) short-tandem repeat signals, we identified seven novel suggestive Parkinson's disease short-tandem repeat risk loci (α = 5.3 × 10-6). Of these, especially a short-tandem repeat near MEIOSIN showed consistent evidence for association across datasets. CCAR2, NCOR1 and one novel suggestive locus identified here (LINC01012) emerged from colocalization analyses showing evidence for a shared causal short-tandem repeat variant affecting both Parkinson's disease risk and cis DNA methylation in brain. Larger studies, ideally using short-tandem repeats called from whole-sequencing data, are needed to more fully investigate their role in Parkinson's disease.

Utilising SNP Association Analysis as a Prospective Approach for Personalising Androgenetic Alopecia Treatment.

Androgenetic alopecia (AGA) is a prevalent, multifactorial form of hair loss involving complex aetiological factors, such as altered androgen regulation and energy metabolism. Existing treatments offer limited success, thus highlighting the need for advanced, personalised therapeutic strategies. This study focuses on correlating the genetic mechanisms of AGA with molecular targets involved in the response to current treatment modalities. An anonymised database including 26,607 patients was subjected to analysis. The dataset included information on patients' genotypes in 26 single nucleotide polymorphisms (SNPs), specifically, and diagnosed AGA grades, representing a broad range of ethnic backgrounds. In our sample, 64.6% of males and 35.4% of females were diagnosed with female pattern hair loss. This distribution aligns well with prior studies, thus validating the representativeness of our dataset. AGA grading was classified using the Hamilton-Norwood and Ludwig scales, although no association was found to the grade of the disease. SNP association analysis revealed eight SNPs, namely rs13283456 (PTGES2), rs523349 (SRD5A2), rs1800012 (COL1A1), rs4343 (ACE), rs10782665 (PTGFR), rs533116 (PTGDR2), rs12724719 (CRABP2) and rs545659 (PTGDR2), to be statistically significant with a p-value below 0.05. The study establishes a preliminary association between eight specific SNPs and AGA. These genetic markers offer insights into the variability of therapeutic responses, thus underlining the importance of personalised treatment approaches. Our findings show the potential for more targeted research to understand these SNPs' and further roles in AGA pathophysiology and in modulating treatment response.

Enhanced polygenic risk score incorporating gene-environment interaction suggests the association of major depressive disorder with cardiac and lung function.

Depression has been linked to an increased risk of cardiovascular and respiratory diseases; however, its impact on cardiac and lung function remains unclear, especially when accounting for potential gene-environment interactions. We developed a novel polygenic and gene-environment interaction risk score (PGIRS) integrating the major genetic effect and gene-environment interaction effect of depression-associated loci. The single nucleotide polymorphisms (SNPs) demonstrating major genetic effect or environmental interaction effect were obtained from genome-wide SNP association and SNP-environment interaction analyses of depression. We then calculated the depression PGIRS for non-depressed individuals, using smoking and alcohol consumption as environmental factors. Using linear regression analysis, we assessed the associations of PGIRS and conventional polygenic risk score (PRS) with lung function (N = 42886) and cardiac function (N = 1791) in the subjects with or without exposing to smoking and alcohol drinking. We detected significant associations of depression PGIRS with cardiac and lung function, contrary to conventional depression PRS. Among smokers, forced vital capacity exhibited a negative association with PGIRS (β = -0.037, FDR = 1.00 × 10-8), contrasting with no significant association with PRS (β = -0.002, FDR = 0.943). In drinkers, we observed a positive association between cardiac index with PGIRS (β = 0.088, FDR = 0.010), whereas no such association was found with PRS (β = 0.040, FDR = 0.265). Notably, in individuals who both smoked and drank, forced expiratory volume in 1-second demonstrated a negative association with PGIRS (β = -0.042, FDR = 6.30 × 10-9), but not with PRS (β = -0.003, FDR = 0.857). Our findings underscore the profound impact of depression on cardiac and lung function, highlighting the enhanced efficacy of considering gene-environment interactions in PRS-based studies.

Genome-wide analysis reveals that the cytochrome P450 family 7 subfamily B member 1 gene is implicated in growth traits in Rasa Aragonesa ewes.

Sheep are very well adapted to changing environments and are able to produce and reproduce with low inputs in feed and water better than other domestic ruminants. Indeed, the ewe body condition score (BCS) and live weight (LW) play a significant role in productive and reproductive performance. This work conducts a genome-wide association study (GWAS) to detect genetic variants associated with growth traits in 225 adult ewes of the Rasa Aragonesa breed by using the genotypes from 50k and HD Illumina Ovine BeadChip. These ewes were measured for LW, BCS and growth rate (GR) for 2years, from January to September. Corrected phenotypes for BCS, LW and GR were estimated and used as input for the GWAS. Only one single nucleotide polymorphism (SNP) rs425509273 in chromosome 9 (OAR9), associated with the GR, overcame the genome-wise significance level. One, three and nine SNPs were associated at the chromosome-wise level (FDR 10%) for traits BCS, LW and GR, respectively. The cytochrome P450 family 7 subfamily B member 1 (CYP7B1) candidate gene, located 83kb upstream from SNP rs425509273 in OAR9, was partially isolated and Sanger-sequenced. Fifteen polymorphisms comprising 12 SNPs, two indels and one polyC, were detected in promoter, exon 1, 3, 5, and intron 1-3 region. The SNP association analysis of the polymorphisms located close to the transcription start site (TSS) showed that a 22bp insertion located at -58 nucleotides from the TSS (indel (-58)), a polyC (-25), and two A/G SNPs (SNP3 (-114) and SNP5 (-63)) were associated with the GR trait, whereas only the indel (-58) was associated with the BCS trait. The haplotype analysis confirmed these results. The functional characterisation of the polymorphisms at CYP7B1 gene in liver by real-time quantitative PCR analysis confirmed that the mutations in the promoter region affected CYP7B1 gene expression. Our results demonstrated the involvement of the CYP7B1 gene promoter on GR and BCS traits in Rasa Aragonesa. These findings suggest that variations in ovine CYP7B1 may serve as potential genetic markers to be used in breeding programmes to improve growth characteristics that could influence reproductive traits.

Combined CRISPRi and proteomics screening reveal a cohesin-CTCF-bound allele contributing to increased expression of RUVBL1 and prostate cancer progression

Genome-wide association studies along with expression quantitative trait locus (eQTL) mapping have identified hundreds of single-nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9,133 guide RNAs (gRNAs) to cover 2,166 candidate SNP loci implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in screening (FDR<0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856G allele (p value= 1.2×10-16 and 3.2×10-7, respectively). Subsequent eQTL analysis revealed that the G allele is associated with increased RUVBL1 expression in multiple datasets. Further CRISPRi and xCas9 base editing confirmed that the rs60464856G allele leads to elevated RUVBL1 expression. Furthermore, SILAC-based proteomic analysis demonstrated allelic binding of cohesin subunits at the rs60464856 region, where the HiC dataset showed consistent chromatin interactions in prostate cell lines. RUVBL1 depletion inhibited PCa cell proliferation and tumor growth in a xenograft mouse model. Gene-set enrichment analysis suggested an association of RUVBL1 expression with cell-cycle-related pathways. Increased expression of RUVBL1 and activation of cell-cycle pathways were correlated with poor PCa survival in TCGA datasets. Our CRISPRi screening prioritized about one hundred regulatory SNPs essential for prostate cell proliferation. In combination with proteomics and functional studies, we characterized the mechanistic role of rs60464856 and RUVBL1 in PCa progression.

Immunity gene IFITM3 variant: relation to cognition and Alzheimer pathology

AbstractBackgroundIFITM3, an innate immune response protein and inhibitor of viral infection, was reported to modulate amyloid‐β production in Alzheimer’s disease (AD). We aimed to identify single‐nucleotide polymorphisms (SNPs) in IFITM3 associated with cognition and AD biomarkers.MethodWe used genetic, longitudinal cognition and AD biomarker data from Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 1,565) and AddNeuroMed (N = 633) as discovery and replication samples, respectively. First, we performed gene‐based association analysis of SNPs in IFITM3 with cognitive performance. Second, we performed SNP‐based association analysis in IFITM3 with cognitive decline and AD biomarkers from amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI).ResultGene‐based association analysis showed that IFITM3 was significantly associated with cognitive performance (permutation‐corrected p = 1.25×10−3). Particularly, among two SNPs (rs10751647, rs2091850) in IFITM3 significantly associated with cognitive performance, rs10751647 was associated with cognitive decline in ADNI, which was replicated in AddNeuroMed. In addition, rs10751647 was significantly associated with amyloid‐β deposition measured by amyloid PET scan, CSF phosphorylated tau levels, and entorhinal cortical thickness measured by MRI scan in ADNI. The association of rs10751647 with entorhinal cortical thickness was replicated in AddNeuroMed. Participants with minor alleles (C) of rs10751647 have less cognitive decline, less amyloid and tau burden, and less brain atrophy. eQTL analysis showed that rs10751647 is associated with IFITM3 expression levels in blood and brain.ConclusionThis suggests that rs10751647 in IFITM3 is associated with less vulnerability for cognitive decline and AD biomarkers, providing mechanistic insight regarding involvement of immune activity and infection in AD.

Simultaneous selection of multiple important single nucleotide polymorphisms in familial genome wide association studies data

We propose a resampling-based fast variable selection technique for detecting relevant single nucleotide polymorphisms (SNP) in a multi-marker mixed effect model. Due to computational complexity, current practice primarily involves testing the effect of one SNP at a time, commonly termed as ‘single SNP association analysis’. Joint modeling of genetic variants within a gene or pathway may have better power to detect associated genetic variants, especially the ones with weak effects. In this paper, we propose a computationally efficient model selection approach—based on the e-values framework—for single SNP detection in families while utilizing information on multiple SNPs simultaneously. To overcome computational bottleneck of traditional model selection methods, our method trains one single model, and utilizes a fast and scalable bootstrap procedure. We illustrate through numerical studies that our proposed method is more effective in detecting SNPs associated with a trait than either single-marker analysis using family data or model selection methods that ignore the familial dependency structure. Further, we perform gene-level analysis in Minnesota Center for Twin and Family Research (MCTFR) dataset using our method to detect several SNPs using this that have been implicated to be associated with alcohol consumption.

Association of Vitamin D Receptor Gene Polymorphisms with Cardiometabolic Phenotypes in Hispanics: A Life Course Approach.

The vitamin D receptor (VDR) is vital for maintaining calcium and phosphate balance and regulating bone metabolism. Recent research has suggested that VDR also plays an essential role in metabolic diseases. Previous studies on non-Hispanic whites have shown that VDR single nucleotide polymorphisms (SNP) are associated with cardiometabolic phenotypes. However, the association between VDR SNPs and cardiometabolic traits in Hispanics remains unclear. This study investigated the association between VDR SNPs and cardiometabolic phenotypic data in self-reported Hispanics (n = 1610) from the Arizona Insulin Resistance registry and Sangre Por Salud Biobank. The study population was predominantly female (66.4%) with a mean age of 40 ± 14 years (n = 121 <18 years) and an average body mass index (BMI) of 29.8 ± 6.3 kg/m2. We performed a genotyping association analysis of VDR SNPs (Taq1-rs731236, Fok1-rs2228570 and Apa1-rs7975232) with cardiometabolic traits using linear regression models. The results showed that Taq1 and Apa1 were strongly associated with systolic blood pressure (SBP) in children (<18 years), while Fok1 was associated with measures of adiposity, including fat mass, waist circumference, and BMI. In age-stratified adult (≥18 years) models, Taq1 was strongly associated with hemoglobin A1c, while Apa1 was associated with BMI and fasting glucose. Fok1 had no significant associations in the adult models. In conclusion, the VDR SNPs were associated with several cardiometabolic phenotypes in this Hispanic sample, but the type and strength of the associations varied by age group.

Intergenic variants, rs1200114 and rs1200108 are genetically associated along with a decreased ATP1B1 expression in Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is an age-related, bilateral corneal condition, characterized by apoptosis of the terminally differentiated endothelial cells. A genome-wide association study (GWAS) conducted in the European population in 2017, identified a new single nucleotide polymorphism (SNP), rs1200114 in the intergenic region between long intergenic non-protein coding RNA 970 (LINC00970) and ATPase Na+/K+ transporting subunit beta 1 (ATP1B1). The major focus of the current study is to understand the genetic association of this intergenic variant, rs1200114 with FECD in the Indian population. Sanger sequencing followed by statistical analysis indicated a significant difference in the allelic frequency between controls and cases (P = 0.01) with the minor allele ‘G’ of rs1200114 imparting a 1.64 fold increased risk for the disease. Luciferase reporter assay revealed no significant difference in the luciferase activity between allele ‘A’ and ‘G’ of rs1200114. However, quantitative RT-PCR assay revealed lower expression of ATP1B1 in FECD subjects compared with controls (P = 0.007). Therefore, to find whether another nearby SNP imparts regulatory effect, tag SNP association analysis was carried out; which revealed a significant association of another SNP, rs1200108, present in the intergenic region between LINC00970 and ATP1B1 with FECD (P = 0.009). The protective allele ‘A’ of rs1200108 displayed reduced reporter activity as opposed to the risk allele ‘G’ (P = 0.014). Furthermore, haplotype ‘A-A’ of rs1200108 - rs1200114 was present at a higher frequency in control subjects, suggesting it as a protective haplotype. Altogether, this study inferred the genetic association of rs1200114 and rs1200108 along with the decreased expression of ATP1B1 related to FECD pathogenesis in the Indian population.

Polymorphisms in TRIB2 and CAPRIN2 Genes Contribute to the Susceptibility to High Myopia-Induced Cataract in Han Chinese Population.

BACKGROUND Myopia has been shown to be associated with many pathological complications including cataracts, and previous evidence supported that high myopia facilitates the formation of cataracts. However, no studies have identified a link between the genetic susceptibility of high myopia-induced cataracts (HMC) and the underlying genetic mechanisms. Our study aimed to determine how the TRIB2 and CAPRIN2 genes correlate to the risk of HMC. MATERIAL AND METHODS In total, we successfully recruited 3162 participants, including 1026 participants with high myopia and cataracts and 2136 controls with high myopia only. For genotyping, 22 tag single nucleotide polymorphisms (SNPs) in TRIB2 and CAPRIN2 genes were chosen. Single marker association analysis and functional effects of significant SNPs were carried out. RESULTS Strong correlation signals were captured for SNP rs890069 (χ²=22.13, P=2.55×10-6) in TRIB2 and SNP rs17739338 (χ²=16.07, P=6.10×10-5) in CAPRIN2. In patients with high myopia, the C allele at SNP rs890069 was strongly linked to cataract risk (OR [95% CI]=1.36 [1.20-1.55]). In patients with high myopia, the T allele at SNP rs17739338 was significantly related to a lower risk of cataract (OR [95% CI]=0.54 [0.40-0.74]). In different types of human tissues, SNPs rs890069 and rs17739338 were found to be significantly correlated to the levels of TRIB2 and CAPRIN2 gene expression. CONCLUSIONS Our study indicated that both TRIB2 and CAPRIN2 genes conferred the susceptibility to cataract in patients with high myopia and Chinese Han ancestry. Future research remains necessary for fully understanding the pathogenic mechanisms and genetic characteristics of cataract.

Molecular Marker-Assisted Selection of ABCG2, CD44, SPP1 Genes Contribute to Milk Production Traits of Chinese Holstein.

Based on our results of genome-wide association analysis, we performed gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis; three candidate genes (ABCG2, CD44, SPP1) were screened in this study for SNPs association analysis with production traits in 999 Holstein cattle. In this research, flight mass spectrometry genotyping was used to detect the polymorphism of SNP seats. It was shown that four, four, and two single nucleotide polymorphisms (SNP) loci were detected for the ABCG2, CD44, and SPP1 genes, respectively, and the different genotypes of these 10 SNPs significantly affected the milk production performance of Chinese Holstein cattle in terms of milk yield, milk fat percentage, milk protein percentage, somatic cell score, and urea nitrogen content. Among them, ABCG2-G.80952G &gt; T locus, ABCG2-G.120017G &gt; A locus and CD44-G.2294G &gt; C locus had significant effects on somatic cell score (p &lt; 0.01). Cows with GG genotypes at ABCG2-G.80952G &gt; T locus, AA and GG genotypes at ABCG2-G.120017G &gt; A locus, and GG genotypes at CD44-G.2294G &gt; C locus had lower somatic cell scores. The present study elucidated that ABCG2, CD44, and SPP1 could be selected for marker-assisted selection and will benefit for future precise molecular breeding.

Polymorphism of prolactin (PRL) gene exon5 and its association with egg production in IPB-D1 chickens.

The prolactin (PRL) gene regulates the egg production and incubation in laying chickens. Local chickens' reproductive systems will disrupt as a result of the incubation period activity, and they will lay fewer eggs. This study aimed to determine the prolactin gene polymorphism in IPB-D1 hens and its relationship to egg production. The polymorphism of the exon5 prolactin gene was examined on 112 samples of the IPB-D1 chicken DNA collection from the Division of Animal Genetics and Breeding, Faculty of Animal Sciences, IPB University. By performing the phenol-chloroform method, the genomic DNA was obtained. A polymerase chain reaction (PCR) product with a size of 557 bp was produced as a result of the DNA amplification. Three single-nucleotide sequences were discovered. Three single-nucleotide polymorphisms (SNPs), g.7835A G, g.7886A T, and g.8052T C, were found in exon5 of the PRL gene. Each mutation was polymorphic and in Hardy-Weinberg equilibrium. The point mutation g.8052T C significantly impacted the egg production of IPB-D1 chickens, according to the SNP association analysis on egg production, and may serve as a marker to enhance the selection for the features of egg production in IPB-D1 chickens.

Association analysis of single-nucleotide polymorphism in prolactin and its receptor with productive and body conformation traits in Liaoning cashmere goats.

The results of this study showed that the single-nucleotide polymorphism (SNP) sites of the PRL and PRLR genes have a certain association with the milk production performance, body size and cashmere performance of Liaoning cashmere goats (LCGs). Through our designed experiment, the potential SNPs of LCG were detected by sequence alignment, and two SNPs were found on two genes. The CC genotype of the PRL gene is the dominant genotype among the three genotypes. The GG genotype of the PRLR gene is the dominant genotype among the two genotypes. At the same time, the two genotypes also have good performance in cashmere production and body size. Through the screening of haplotype combination, the milk fat rate 7.6 %, the milk protein rate 5.6 %, the milk somatic cell number 1500 10 mL, the cashmere fineness 15.75 m, the chest girth 105 cm, the chest depth 33 cm, and the waist height 67.5 cm are considered as screening indexes for comprehensive production performance of Liaoning cashmere goats. It is concluded that the GCGC type is the dominant haplotype combination. According to our research data, we found that the biological indicators of Liaoning cashmere goat milk are higher than the national standards, so we think it is very significant to study the milk production performance of our experiment. Further research can be done on goat milk production and body conformation traits around PRL gene and PRLR gene.

Circulating N-Terminal Probrain Natriuretic Peptide Levels in Relation to Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study.

Mendelian randomization was used to evaluate the potential causal association between N-terminal probrain natriuretic peptide (NT-proBNP) and ischemic stroke based on summary statistics data from large-scale genome-wide association studies. Three single-nucleotide polymorphisms (SNPs) rs198389, rs13107325, and rs11105306 associated with NT-proBNP levels found in large general populations and in patients with acute heart disease were used as instrumental variables. The results of genetic association analysis of each single SNP show that there is no significant association between NT-proBNP levels and ischemic stroke or its subtypes, whereas rs198389 alone has a suggestive association with large-artery atherosclerosis stroke. The MR analysis of three SNPs shows that NT-proBNP levels may reduce the risk of small-vessel occlusion stroke suggestively. This genetic analysis provides insights into the pathophysiology and treatment of ischemic stroke.

Immunity gene IFITM3 variant: Relation to cognition and Alzheimer's disease pathology.

IntroductionWe investigated single‐nucleotide polymorphisms (SNPs) in IFITM3, an innate immunity gene and modulator of amyloid beta in Alzheimer's disease (AD), for association with cognition and AD biomarkers.MethodsWe used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1565) and AddNeuroMed (N = 633) as discovery and replication samples, respectively. We performed gene‐based association analysis of SNPs in IFITM3 with cognitive performance and SNP‐based association analysis with cognitive decline and amyloid, tau, and neurodegeneration biomarkers for AD.ResultsGene‐based association analysis showed that IFITM3 was significantly associated with cognitive performance. Particularly, rs10751647 in IFITM3 was associated with less cognitive decline, less amyloid and tau burden, and less brain atrophy in ADNI. The association of rs10751647 with cognitive decline and brain atrophy was replicated in AddNeuroMed.DiscussionThis suggests that rs10751647 in IFITM3 is associated with less vulnerability for cognitive decline and AD biomarkers, providing mechanistic insight regarding involvement of immunity and infection in AD.Highlights IFITM3 is significantly associated with cognitive performance.rs10751647 in IFITM3 is associated with cognitive decline rates with replication.rs10751647 is associated with amyloid beta load, cerebrospinal fluid phosphorylated tau levels, and brain atrophy.rs10751647 is associated with IFITM3 expression levels in blood and brain.rs10751647 in IFITM3 is related to less vulnerability to Alzheimer's disease pathogenesis.

BMI1 rs17415557 polymorphism is associated with amyloid-β and rates of cognitive decline in Alzheimer's disease.

Accumulating evidence suggests that BMI1 confers protective effects against Alzheimer's disease (AD). However, the mechanism remains elusive. Given recent pathophysiological evidence, we investigated whether genetic variants in BMI1 is associated with AD biomarkers. We used genetic and AD biomarker data from two independent well-characterized cohorts: Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). First, we performed a gene-based association analysis of single-nucleotide polymorphisms (SNPs) in BMI1 with cerebrospinal fluid (CSF) Aβ1-42 levels. Second, we performed longitudinal association analyses of SNPs with cognitive decline rates using linear mixed-effects models. Gene-based genetic association analysis identified SNPs in BMI1 as being significantly associated with CSF Aβ1-42 levels after adjusting for multiple testing using permutation. Participants with minor alleles of BMI1 rs17415557 with the most significant association have increased CSF Aβ1-42 levels, which was interestingly prominent within amyloid-positive participants. Further analysis identified and replicated the minor allele of rs17415557 as being significantly associated with slower cognitive decline rates in AD. Our findings provide fundamental evidence that BMI1 rs17415557 may serve as a protective mechanism related to AD pathogenesis, which supports the results of previous studies linking BMI1 to protection against AD.

BMI1 is associated with CSF amyloid-\u03b2 and rates of cognitive decline in Alzheimer\u2019s disease

BackgroundAccumulating evidence suggests that BMI1 confers protective effects against Alzheimer’s disease (AD). However, the mechanism remains elusive. Based on recent pathophysiological evidence, we sought for the first time to identify genetic variants in BMI1 as associated with AD biomarkers, including amyloid-β.MethodsWe used genetic, longitudinal cognition, and cerebrospinal fluid (CSF) biomarker data from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). First, we performed a gene-based association analysis of common single nucleotide polymorphisms (SNPs) (minor allele frequency (MAF) > 5%) located within ± 20 kb of the gene boundary of BMI1, an optimal width for including potential regulatory SNPs in the 5′ and 3′ untranslated regions (UTR) of BMI1, with CSF Aβ1-42 levels. Second, we performed cross-sectional and longitudinal association analyses of SNPs in BMI1 with cognitive performance using linear and mixed-effects models. We replicated association of SNPs in BMI1 with cognitive performance in an independent cohort (N=1084), Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP).ResultsGene-based genetic association analysis showed that BMI1 was significantly associated with CSF Aβ1-42 levels after adjusting for multiple testing using permutation (permutation-corrected p value=0.005). rs17415557 in BMI1 showed the most significant association with CSF Aβ1-42 levels. Participants with minor alleles of rs17415557 have increased CSF Aβ1-42 levels compared to those with no minor alleles. Further analysis identified and replicated the minor allele of rs17415557 as being significantly associated with slower cognitive decline rates in AD.ConclusionsOur findings provide fundamental evidence that BMI1 rs17415557 may serve as a protective mechanism related to AD pathogenesis, which supports the results of previous studies linking BMI1 to protection against AD.

Variability in porcine microRNA genes and its association with mRNA expression and lipid phenotypes

BackgroundMature microRNAs (miRNAs) play an important role in repressing the expression of a wide range of mRNAs. The presence of polymorphic sites in miRNA genes and their corresponding 3′UTR binding sites can disrupt canonical conserved miRNA–mRNA pairings, and thus modify gene expression patterns. However, to date such polymorphic sites in miRNA genes and their association with gene expression phenotypes and complex traits are poorly characterized in pigs.ResultsBy analyzing whole-genome sequences from 120 pigs and wild boars from Europe and Asia, we identified 285 single nucleotide polymorphisms (SNPs) that map to miRNA loci, and 109,724 SNPs that are located in predicted 7mer-m8 miRNA binding sites within porcine 3′UTR. In porcine miRNA genes, SNP density is reduced compared with their flanking non-miRNA regions. By sequencing the genomes of five Duroc boars, we identified 12 miRNA SNPs that were subsequently genotyped in their offspring (N = 345, Lipgen population). Association analyses of miRNA SNPs with 38 lipid-related traits and hepatic and muscle microarray expression phenotypes recorded in the Lipgen population were performed. The most relevant detected association was between the genotype of the rs319154814 (G/A) SNP located in the apical loop of the ssc-miR-326 hairpin precursor and PPP1CC mRNA levels in the liver (q-value = 0.058). This result was subsequently confirmed by qPCR (P-value = 0.027). The rs319154814 (G/A) genotype was also associated with several fatty acid composition traits.ConclusionsOur findings show a reduced variability of porcine miRNA genes, which is consistent with strong purifying selection, particularly in the seed region that plays a critical role in miRNA binding. Although it is generally assumed that SNPs mapping to the seed region are those with the most pronounced consequences on mRNA expression, we show that a SNP mapping to the apical region of ssc-miR-326 is significantly associated with hepatic mRNA levels of the PPP1CC gene, one of its predicted targets. Although experimental confirmation of such an interaction is reported in humans but not in pigs, this result highlights the need to further investigate the functional effects of miRNA polymorphisms that are located outside the seed region on gene expression in pigs.

Genome-Wide Association Study Demonstrates the Role Played by the CD226 Gene in Rasa Aragonesa Sheep Reproductive Seasonality.

Simple SummaryTo elucidate the genetic basis of reproductive seasonality in Rasa Aragonesa sheep breed, we performed a genome-wide association study (GWAS) in order to detect single nucleotide polymorphisms (SNPs) or regions associated with traits related to ovarian function and behavioural signs of estrous. The GWAS included 205 ewes with genotypes for 583882 SNPs. Only one SNP overcame the genome-wide significance level. Nine potential SNPs overcame the chromosome-wise significance level (FDR 10%). Gene annotation demonstrated that CD226 molecule (CD226) and neuropeptide Y (NPY) genes that could be involved in reproductive seasonality were close to the significant SNPs. To validate the results, we sequenced the entire coding region of the NPY gene and four exons of the CD226 gene to search for polymorphisms that could be involved in the phenotypes studied. Two synonymous and two nonsynonymous SNPs in the NPY and CD226 genes, respectively, were genotyped in the whole population. We demonstrated that the AA genotype of the SNP rs404360094 located in exon 3 of the CD226 gene was associated with higher and lower total days of anoestrus and oestrous cycling months, respectively. Therefore, this SNP could be utilized as a genetic marker for assisted selection marker to reduce seasonality.A genome-wide association study (GWAS) was used to identify genomic regions influencing seasonality reproduction traits in Rasa Aragonesa sheep. Three traits associated with either ovarian function based on blood progesterone levels (total days of anoestrus and progesterone cycling months) or behavioral signs of oestrous (oestrous cycling months) were studied. The GWAS included 205 ewes genotyped using the 50k and 680k Illumina Ovine Beadchips. Only one SNP associated with the progesterone cycling months overcame the genome-wide significance level (rs404991855). Nine SNPs exhibited significant associations at the chromosome level, being the SNPs rs404991855 and rs418191944, that are located in the CD226 molecule (CD226) gene, associated with the three traits. This gene is related to reproductive diseases. Two other SNPs were located close to the neuropeptide Y (NPY) gene, which is involved in circadian rhythms. To validate the GWAS, partial characterization of both genes by Sanger sequencing, and genotyping of two synonymous and two nonsynonymous SNPs in the NPY and CD226 genes, respectively, were performed. SNP association analysis showed that only SNP rs404360094 in the exon 3 of the CD226 gene, which produces an amino acid substitution from asparagine (uncharged polar) to aspartic acid (acidic), was associated with the three seasonality traits. Our results suggest that the CD226 gene may be involved in the reproductive seasonality in Rasa Aragonesa.