Genome-wide association studies (GWAS) have revealed numerous loci associated with stroke. However, the underlying mechanisms at these loci in the pathogenesis of stroke and effective stroke drug ...targets are elusive. Therefore, we aimed to identify causal genes in the pathogenesis of stroke and its subtypes.
Utilizing multidimensional high-throughput data generated, we integrated proteome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and Bayesian colocalization analysis to prioritize genes that contribute to stroke and its subtypes risk via affecting their expression and protein abundance in brain and blood.
Our integrative analysis revealed that ICA1L was associated with small-vessel stroke (SVS), according to robust evidence at both protein and transcriptional levels based on brain-derived data. We also identified NBEAL1 that was causally related to SVS via its cis-regulated brain expression level. In blood, we identified 5 genes (MMP12, SCARF1, ABO, F11, and CKAP2) that had causal relationships with stroke and stroke subtypes.
Together, via using an integrative analysis to deal with multidimensional data, we prioritized causal genes in the pathogenesis of SVS, which offered hints for future biological and therapeutic studies.
The constitution and skin type of individuals are influenced by various factors. Recently, the influence of genetic predispositions on these has been emphasized. To date, genome‐wide association ...studies (GWAS) have shown several single nucleotide polymorphisms (SNPs) that affect individual's constitution and skin type. However, these studies have mainly focused on the Caucasian population, and only a few association analyses with the constitution and skin type of individuals involving a Japanese population have been conducted. In this study, we conducted a GWAS analysis of 9 phenotypes regarding the constitution or skin type of 1108 Japanese women based on a questionnaire. As a result, in addition to SNPs known to be involved in phenotypes in the past, we discovered new SNPs and genetic regions related to darkness of pigmented spots, skin flushing, frequency of rough skin and responsiveness to cosmetics.
In this study, we conducted a GWAS analysis of 9 phenotypes for the constitution or skin type of Japanese women, and found new SNPs and gene regions associated with the darkness of pigment spots, skin flushing, frequency of rough skin and responsiveness to cosmetics.
Summary
Aims
Although converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their ...links is less well characterized. Traditional SNP‐based genome‐wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies.
Methods
Taking advantage of large‐scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene‐based analysis implemented in VEGAS2 and Fisher's meta‐analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD‐ or IS‐associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified.
Results
16 AD‐IS pleiotropic genes surpassed the cutoff for Bonferroni‐corrected significance. Notably, MS4A4A and TREM2, two established AD‐susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature‐based knowledge, most are immune‐relevant genes (EPHA1, MS4A4A, UBE2L3 and TREM2), implicating crucial roles of the immune system in the pathogenesis of AD and IS.
Conclusions
The observation that AD and IS had shared disease‐associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.
The level of response (LR) to alcohol as measured with the Self‐Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to ...four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome‐wide association study (GWAS) in the African‐American (COGA‐AA, N = 1527 from 309 families) and European‐American (COGA‐EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE‐T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE‐5 (the first five times of drinking). We then meta‐analyzed the two COGA subsamples (COGA‐AA + EA). Both SRE‐T and SRE‐5 were modestly heritable (h2: 21%‐31%) and genetically correlated with alcohol dependence (AD) and DSM‐IV AD criterion count (rg: 0.35‐0.76). Genome‐wide significant associations were observed (SRE‐T: chromosomes 6, rs140154945, COGA‐EA P = 3.30E‐08 and 11, rs10647170, COGA‐AA+EA P = 3.53E‐09; SRE‐5: chromosome13, rs4770359, COGA‐AA P = 2.92E‐08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE‐T and SRE‐5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM‐IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.
We performed GWAS of the Self‐Report of the Effects of alcohol (SRE) scores using COGA samples. Three loci were genomewide significant and one was replicated. Functional analyses suggested that the chromosome 6 locus is an eQTL for KIF25. COGA SRE GWAS derived polygenic risk scores predicted variances in alcohol dependence (AD) and DSM‐IV AD criterion count. This study highlights the genetic contribution of SRE to the etiology of alcohol use disorders.
The genetic architecture of Alzheimer's disease (AD) is only partially understood.
We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., ...cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome–sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families.
We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10−10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10−10).
Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.
Summary
Kernel size‐related traits are the most direct traits correlating with grain yield. The genetic basis of three kernel traits of maize, kernel length (KL), kernel width (KW) and kernel ...thickness (KT), was investigated in an association panel and a biparental population. A total of 21 single nucleotide polymorphisms (SNPs) were detected to be most significantly (P < 2.25 × 10−6) associated with these three traits in the association panel under four environments. Furthermore, 50 quantitative trait loci (QTL) controlling these traits were detected in seven environments in the intermated B73 × Mo17 (IBM) Syn10 doubled haploid (DH) population, of which eight were repetitively identified in at least three environments. Combining the two mapping populations revealed that 56 SNPs (P < 1 × 10−3) fell within 18 of the QTL confidence intervals. According to the top significant SNPs, stable‐effect SNPs and the co‐localized SNPs by association analysis and linkage mapping, a total of 73 candidate genes were identified, regulating seed development. Additionally, seven miRNAs were found to situate within the linkage disequilibrium (LD) regions of the co‐localized SNPs, of which zma‐miR164e was demonstrated to cleave the mRNAs of Arabidopsis CUC1, CUC2 and NAC6 in vitro. Overexpression of zma‐miR164e resulted in the down‐regulation of these genes above and the failure of seed formation in Arabidopsis pods, with the increased branch number. These findings provide insights into the mechanism of seed development and the improvement of molecular marker‐assisted selection (MAS) for high‐yield breeding in maize.
In two studies (total N = 829), we assessed civilian implicit associations with police using four modified Implicit Association Tests (IAT). Across studies and IATs, individuals harbored stronger ...negative implicit associations (associating police with fear/bad) than positive implicit associations (associating police with safety/good). The predictive validity of the implicit associations and magnitude of D scores varied across IAT. In Study 1, the IATs involving categorization of police-related (vs. everyday) symbols were most sensitive, but the versions involving categorization of police (vs. civilian) models provided more evidence for predictive validity. In Study 2, the IAT involving categorization of emotional words (safety/fear) was most sensitive, but the version involving categorization of evaluative words (good/bad) provided more evidence for predictive validity. In both studies, we also assessed individual differences (race, political affiliation) in implicit associations. The findings prompt the need to further examine the underlying cognitive components of civilian attitudes toward police and emphasize the importance of developing several IATs when assessing implicit attitudes.
The relationship between germline genetic variation and breast cancer survival is largely unknown, especially in understudied minority populations who often have poorer survival. Genome-wide ...association studies (GWAS) have interrogated breast cancer survival but often are underpowered due to subtype heterogeneity and clinical covariates and detect loci in non-coding regions that are difficult to interpret. Transcriptome-wide association studies (TWAS) show increased power in detecting functionally relevant loci by leveraging expression quantitative trait loci (eQTLs) from external reference panels in relevant tissues. However, ancestry- or race-specific reference panels may be needed to draw correct inference in ancestrally diverse cohorts. Such panels for breast cancer are lacking.
We provide a framework for TWAS for breast cancer in diverse populations, using data from the Carolina Breast Cancer Study (CBCS), a population-based cohort that oversampled black women. We perform eQTL analysis for 406 breast cancer-related genes to train race-stratified predictive models of tumor expression from germline genotypes. Using these models, we impute expression in independent data from CBCS and TCGA, accounting for sampling variability in assessing performance. These models are not applicable across race, and their predictive performance varies across tumor subtype. Within CBCS (N = 3,828), at a false discovery-adjusted significance of 0.10 and stratifying for race, we identify associations in black women near AURKA, CAPN13, PIK3CA, and SERPINB5 via TWAS that are underpowered in GWAS.
We show that carefully implemented and thoroughly validated TWAS is an efficient approach for understanding the genetics underpinning breast cancer outcomes in diverse populations.
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