Intergenic Single Nucleotide Polymorphisms Research Articles

A genome-wide association study identifies genetic determinants of hemoglobin glycation index with implications across sex and ethnicity

IntroductionWe investigated the genetic determinants of variation in the hemoglobin glycation index (HGI), an emerging biomarker for the risk of diabetes complications.MethodsWe conducted a genome-wide association study (GWAS) for HGI in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 7,913) using linear regression and additive genotype encoding on variants with minor allele frequency greater than 3%. We conducted replication analyses of top findings in the Atherosclerosis Risk in Communities (ARIC) study with inverse variance-weighted meta-analysis. We followed up with stratified GWAS analyses by sex and self-reported race.ResultsIn ACCORD, we identified single nucleotide polymorphisms (SNPs) associated with HGI, including a peak with the strongest association at the intergenic SNP rs73407935 (7q11.22) (P = 5.8e−10) with a local replication in ARIC. In black individuals, the variant rs10739419 on chromosome 9 in the Whirlin (WHRN) gene formally replicated (meta-P = 2.2e−9). The SNP-based heritability of HGI was 0.39 (P< 1e−10). HGI had significant sex-specific associations with SNPs in or near GALNT11 in women and HECW2 in men. Finally, in Hispanic participants, we observed genome-wide significant associations with variants near USF1 and NXNL2/SPIN1.DiscussionMany HGI-associated SNPs were distinct from those associated with fasting plasma glucose or HbA1c, lending further support for HGI as a distinct biomarker of diabetes complications. The results of this first evaluation of the genetic etiology of HGI indicate that it is highly heritable and point to heterogeneity by sex and race.

Unraveling the genetic architecture of blood unfolded p-53 among non-demented elderlies: novel candidate genes for early Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a heritable neurodegenerative disease whose long asymptomatic phase makes the early diagnosis of it pivotal. Blood U-p53 has recently emerged as a superior predictive biomarker for AD in the early stages. We hypothesized that genetic variants associated with blood U-p53 could reveal novel loci and pathways involved in the early stages of AD.ResultsWe performed a blood U-p53 Genome-wide association study (GWAS) on 484 healthy and mild cognitively impaired subjects from the ADNI cohort using 612,843 Single nucleotide polymorphisms (SNPs). We performed a pathway analysis and prioritized candidate genes using an AD single-cell gene program. We fine-mapped the intergenic SNPs by leveraging a cell-type-specific enhancer-to-gene linking strategy using a brain single-cell multimodal dataset. We validated the candidate genes in an independent brain single-cell RNA-seq and the ADNI blood transcriptome datasets. The rs279686 between AASS and FEZF1 genes was the most significant SNP (p-value = 4.82 × 10–7). Suggestive pathways were related to the immune and nervous systems. Twenty-three candidate genes were prioritized at 27 suggestive loci. Fine-mapping of 5 intergenic loci yielded nine cell-specific candidate genes. Finally, 15 genes were validated in the independent single-cell RNA-seq dataset, and five were validated in the ADNI blood transcriptome dataset.ConclusionsWe underlined the importance of performing a GWAS on an early-stage biomarker of AD and leveraging functional omics datasets for pinpointing causal genes in AD. Our study prioritized nine genes (SORCS1, KIF5C, TMEFF2, TMEM63C, HLA-E, ATAT1, TUBB, ARID1B, and RUNX1) strongly implicated in the early stages of AD.

Abstract 16731: Post-GWAS Functional Analysis of CBLN2 Locus Reveals the Role of CUX1 in the Inflammatory Pathogenesis of Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a complex and deadly pulmonary vascular disease highly relevant to genetic susceptibility and acquired inflammatory triggers. Chr18q22.3 near cerebellin 2 precursor (CBLN2) gene is the first genetic locus identified by Genome-wide Association Study (GWAS) that is significantly associated with PAH risk in the European population. This locus includes closely linked non-coding intergenic single nucleotide polymorphisms (SNPs) downstream of CBLN2. Although CBLN2 is upregulated in PAH and causes pulmonary vascular dysfunction, it remains unknown how these non-coding SNPs remotely affect CBLN2 and in turn, alter the genetic susceptibility of PAH. Methods and Results: We combined Hi-C chromatin interaction analysis, electrophoretic mobility shift assay, and SNP genotype-PAH correlation analysis with the All of Us database (N=20,343). In doing so, we identified rs11151770(A/G) as a PAH-associated functional SNP (fSNP), among 19 haplotype SNPs in linkage disequilibrium with the associated CBLN2 locus. The genomic region containing rs11151770(A/G) exhibited long-range chromatin interaction with the CBLN2 promotor. Proteomic analysis revealed that nuclear transcription factor Cut-like Homeobox 1 (CUX1) binds specifically to the risk allele A of rs11151770 but not to the non-risk allele G, regulating the expression of CBLN2 as an activator in pulmonary arterial endothelial cells. CUX1-CBLN2 was upregulated by acquired inflammatory PAH triggers IL-1β and IL-6. SNP genotyping in PAH patients (N=159) and non-PAH controls (N=87) showed a 2.2-fold enrichment of the risk allele A only in patients with PAH associated with connective tissue disorders (N=77, p=0.036). These findings supported a pathogenic mechanism of an inflammation-sensitive pathway (CUX1-CBLN2) controlled by an fSNP (risk allele A) underlying the reported genetic association of the CBLN2 locus with PAH risk. Conclusion: Our post-GWAS functional genomics analysis defined a pathogenic CUX1-mediated, fSNP rs11151770(A/G)-controlled, and inflammation-responsive pathway that provides a mechanistic explanation for the GWAS-identified association between genetic variants in CBLN2 locus and PAH susceptibility.

Abstract P1017: Post-GWAS Functional Analysis Of CBLN2 Locus Reveals The Role Of CUX1 In The Inflammatory Pathogenesis Of Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a deadly pulmonary vascular disease highly relevant to genetic susceptibility and acquired pathogenic triggers, especially inflammation. Chr18q22.3 near cerebellin 2 (CBLN2) gene is the first genetic locus identified by Genome-wide Association Study (GWAS) that is significantly associated with PAH risk in population of European ancestry. This locus includes a group of closely linked non-coding intergenic single nucleotide polymorphisms (SNPs) downstream of CBLN2. Although CBLN2 is upregulated in PAH and causes pulmonary vascular dysfunction, it remains unknown how these non-coding SNPs remotely affect CBLN2 and in turn alter the genetic susceptibility of PAH. Methods and Results: We applied Hi-C analysis, combined with electrophoretic mobility shift assay, to identify rs11151770 as a functional SNP (fSNP) characterized with allele-imbalanced nuclear protein binding and chromatin interaction with CBLN2 promoter, among 19 haplotype SNPs in a linkage disequilibrium (LD r 2 >0.8) in CBLN2 locus. As an intergenic non-coding SNP, rs11151770 is located 110 kbp downstream of CBLN2 promoter. Proteomic analysis revealed nuclear transcription factor CUX1 binds specifically to the risk allele A of rs11151770 but not to the non-risk allele C. Acting as the activator for the expression of target gene CBLN2, CUX1 knockdown prevented, but CUX1 overexpression induced, the pathophenotypes of human pulmonary arterial endothelial cells (PAECs) associated with PAH. CUX1-CBLN2 was upregulated by acquired inflammatory PAH trigger IL-1β and was increased in lung tissues extracted from PAH patients. SNP genotyping in PAH patients and non-PAH controls showed a 2.2-fold risk allele A enrichment only in patients with PAH associated with connective tissue disorders, supporting a pathogenic mechanism of an inflammation-sensitive pathway (CUX1-CBLN2) combined with a PAH susceptible genotype (risk allele A of rs11151770) for the manifestation of clinical PAH. Conclusion: Our post-GWAS functional genomics analysis revealed a CUX1-mediated inflammatory pathway and provided a mechanistic explanation for the GWAS-identified association between the genetic variants in CBLN2 locus and PAH pathogenesis.

The association between the CCDC88A gene polymorphism at rs1437396 and alcohol use disorder, with or without major depression disorder.

Girdin is a protein involved in neuronal migration and hippocampal development. It is encoded by the coiled-coil domain-containing 88A (CCDC88A) gene, located on the short arm of chromosome 2 (2p). The CCDC88A gene is modulated by the intergenic single-nucleotide polymorphism (SNP) of the rs1437396, situated 9.5 kb downstream from its transcription stop site. As recent genome-wide research has associated the T allele of the SNP with increased risk of alcohol use disorder (AUD), we wanted to validate this finding in an independent cohort and to test further for an association with comorbid major depressive disorder (MDD). The study included 226 AUD patients (AUD group), 53 patients with comorbid MDD, and 391 controls selected randomly. The participants were genotyped for the rs1437396 polymorphism using the real-time polymerase chain reaction. The association between the rs1437396 polymorphism and increased risk of AUD and AUD+MDD was tested with logistic regression. Our results show significantly higher frequency of the T risk allele in the AUD group (p=0.027) and even higher in the AUD+MDD group (p=0.016). In conclusion, this is the first study that has validated the association between the rs1437396 polymorphism of the CCDC88A gene and AUD with or without MDD. Studies on larger samples of patients are needed to further investigate the mechanism of this association.

Genome-Wide Association Study Identifies Genetic Polymorphisms Associated with Estimated Minimum Effective Concentration of Fentanyl in Patients Undergoing Laparoscopic-Assisted Colectomy.

Sensitivity to opioids varies widely among individuals. To identify potential candidate single-nucleotide polymorphisms (SNPs) that may significantly contribute to individual differences in the minimum effective concentration (MEC) of an opioid, fentanyl, we conducted a three-stage genome-wide association study (GWAS) using whole-genome genotyping arrays in 350 patients who underwent laparoscopic-assisted colectomy. To estimate the MEC of fentanyl, plasma and effect-site concentrations of fentanyl over the 24 h postoperative period were estimated with a pharmacokinetic simulation model based on initial bolus doses and subsequent patient-controlled analgesia doses of fentanyl. Plasma and effect-site MECs of fentanyl were indicated by fentanyl concentrations, estimated immediately before each patient-controlled analgesia dose. The GWAS revealed that an intergenic SNP, rs966775, that mapped to 5p13 had significant associations with the plasma MEC averaged over the 6 h postoperative period and the effect-site MEC averaged over the 12 h postoperative period. The minor G allele of rs966775 was associated with increases in these MECs of fentanyl. The nearest protein-coding gene around this SNP was DRD1, encoding the dopamine D1 receptor. In the gene-based analysis, the association was significant for the SERP2 gene in the dominant model. Our findings provide valuable information for personalized pain treatment after laparoscopic-assisted colectomy.

Genetic Variants Associated with Supernormal Coronary Arteries.

Genetic and medical insights from studies on cardioprotective phenotypes aid the development of novel therapeutics. This study identified genetic variants associated with supernormal coronary arteries using genome-wide association study data and the corresponding genes based on expression quantitative trait loci (eQTL). Study participants were selected from two Korean cohorts according to inclusion criteria that included males with high cardiovascular risk (Framingham risk score ≥ 14, 10-year risk ≥ 16%) but with normal coronary arteries (supernormal group) or coronary artery disease (control group). After screening 12,309 individuals, males meeting the supernormal phenotype (n=72) and age-matched controls (n=94) were enrolled. Genetic variants associated with the supernormal phenotype were identified using Firth's logistic regression, and eQTL was used to evaluate whether the identified variants influence the expression of particular genes in human tissues. Approximately 5 million autosomal variants were tested for association with the supernormal phenotype, and 10 independent loci suggestive of supernormal coronary arteries (p＜5.0 ×10 －5) were identified. The lead variants were seven intergenic single-nucleotide polymorphisms (SNPs), including one near PBX1, and three intronic SNPs, including one in PPFIA4. Of these variants or their proxies, rs9630089, rs6427989, and rs4984694 were associated with expression levels of SLIT1 and ARHGAP19, PPFIA4, and METTL26 in human tissues, respectively. These eQTL results supported their potential biological relevance. This study identified genetic variants and eQTL genes associated with supernormal coronary arteries. These results suggest candidate genes representing potential therapeutic targets for coronary artery disease.

Regulation at Drosophila's Malic Enzyme highlights the complexity of transvection and its sensitivity to genetic background.

Transvection, a type of trans-regulation of gene expression in which regulatory elements on one chromosome influence elements on a paired homologous chromosome, is itself a complex biological phenotype subject to modification by genetic background effects. However, relatively few studies have explored how transvection is affected by distal genetic variation, perhaps because it is strongly influenced by local regulatory elements and chromosomal architecture. With the emergence of the "hub" model of transvection and a series of studies showing variation in transvection effects, it is becoming clear that genetic background plays an important role in how transvection influences gene transcription. We explored the effects of genetic background on transvection by performing two independent genome wide association studies (GWASs) using the Drosophila genetic reference panel (DGRP) and a suite of Malic enzyme (Men) excision alleles. We found substantial variation in the amount of transvection in the 149 DGRP lines used, with broad-sense heritability of 0.89 and 0.84, depending on the excision allele used. The specific genetic variation identified was dependent on the excision allele used, highlighting the complex genetic interactions influencing transvection. We focussed primarily on genes identified as significant using a relaxed P-value cutoff in both GWASs. The most strongly associated genetic variant mapped to an intergenic single nucleotide polymorphism (SNP), located upstream of Tiggrin (Tig), a gene that codes for an extracellular matrix protein. Variants in other genes, such transcription factors (CG7368 and Sima), RNA binding proteins (CG10418, Rbp6, and Rig), enzymes (AdamTS-A, CG9743, and Pgant8), proteins influencing cell cycle progression (Dally and Eip63E) and signaling proteins (Atg-1, Axo, Egfr, and Path) also associated with transvection in Men. Although not intuitively obvious how many of these genes may influence transvection, some have been previously identified as promoting or antagonizing somatic homolog pairing. These results identify several candidate genes to further explore in the understanding of transvection in Men and in other genes regulated by transvection. Overall, these findings highlight the complexity of the interactions involved in gene regulation, even in phenotypes, such as transvection, that were traditionally considered to be primarily influenced by local genetic variation.

Abstract 683: Identification of common germline variants associated with pediatric rhabdomyosarcoma survival: A report from the Children's Oncology Group (COG)

Abstract Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and has one of the poorest survival rates among pediatric cancers, underscoring the need to identify factors which may be leveraged to improve therapeutic options for these individuals. Methods: We carried out a genome-wide association study of overall survival (OS) and event-free survival (EFS) in 920 RMS patients from COG protocols and randomly divided them into discovery (n=642) and replication (n=278) cohorts. Genotyping was conducted using the Illumina OmniExpress or Global Screening Array and imputed using the Haplotype Reference Consortium. We used Cox proportional hazards regression to calculate an adjusted hazard ratio (aHR) and P value for each common variant (minor allele frequency [MAF]>5%) for OS and EFS while adjusting for age at diagnosis, tumor stage, histological subtype, and the top five principal components. Analyses were also conducted by histological subtype: embryonal RMS (ERMS, n=544) and alveolar RMS (ARMS, n=268). Finally, we performed a meta-analysis of the results from the discovery and replication cohorts to generate a summary aHR and P value for each single nucleotide polymorphism (SNP). Results: We identified an intergenic SNP at chr8q21.13 associated with worse RMS EFS across subtypes (aHR=2.08, P=2.80x10-9), which had consistent effects across the discovery (aHR=1.91, P=5.05x10-6) and replication (aHR=2.62, P=7.16x10-5) cohorts. This SNP lies in a region which spans the genomic binding site for GATA2 and GATA3, transcription factors that are recognized to contribute to cancer development. We also identified a significant association between a SNP at chr12q21.1 and worse EFS (aHR=2.04, P=3.35x10-8) with consistent effects across the discovery and replication cohorts. Based on data from the Genotype-Tissue Expression project (GTEx), this SNP is associated with expression of SLCO1B1, a gene which encodes a liver anion transporter linked to RMS treatment-related toxicities. In subtype-specific analyses, we identified a SNP at chr17q21.32 that was significantly associated with worse ARMS OS (129 events; aHR=3.18, P=3.12x10-8; discovery: aHR=3.19, P=6.23x10-4; replication: aHR=3.16, P=1.43x10-3). In GTEx, this SNP is associated with expression and splicing of genes including PITPNM3, KIAA0753, and MED31 across various tissues. No SNPs were significantly associated with ERMS OS or EFS. Conclusion: In the first GWAS of RMS survival outcomes, we identified two SNPs that were significantly associated with worse EFS across RMS subtypes. Further, we identified a SNP that was associated with OS in ARMS patients, a subtype that is associated with worse outcomes. Additional investigation of the impact of these SNPs may further support their consideration for novel risk stratification protocols. Citation Format: Bailey A. Martin-Giacalone, Michael E. Scheurer, Javed Khan, Stephen J. Chanock, Shengchao Alfred Li, Meredith Yeager, Deborah A. Marquez-Do, Donald A. Barkauskas, David Hall, Matthew T. McEvoy, Melissa A. Richard, Pagna Sok, Austin L. Brown, Aniko Sabo, Stephen X. Skapek, Douglas S. Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Philip J. Lupo. Identification of common germline variants associated with pediatric rhabdomyosarcoma survival: A report from the Children's Oncology Group (COG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 683.

Characterization of Potential Molecular Markers in Lac Insect Kerria lacca (Kerr) Responsible for Lac Production.

Simple SummaryLac insect Kerria lacca (Hemiptera, Kerriidae) is widely used to produce lac in tropical and subtropical areas. This species is genomically understudied and there is no information present on single-nucleotide polymorphisms and insertions and deletions of lac insects. This study involves distribution and characterization of molecular markers in K. lacca. Nucleotide substitution frequency and transition to transversion ratio were highest at the late adult stage. The maximum numbers of SNPs and InDels were distributed on chromosome 8 and 1, respectively. Most variants at low frequencies were detected in InDels compared to SNPs. Gene function analysis showed several gene variations, and candidate SNPs that were involved in lac synthesis. This work paves the way to determining further mechanisms involved in increased lac production.Kerria lacca (Kerr) is an important lac insect extensively used in industrial products in the form of resin, wax and dye. The scarce knowledge on molecular markers for K. lacca is a barrier in elucidating genetic information. Our study identified a total of 16,921 single-nucleotide polymorphisms (SNPs), and 6231 insertions and deletions (InDels)—of which, intergenic variation accounted for 41.22% and 56.30%, and exonic variation accounted for 39.10% and 17.46%, of SNPs and InDels, respectively. Observation of SNPs suggested that nucleotide substitution frequency and transition to transversion (Ts/Tv) ratio were highest at the late adult stage, 3.97, compared to at the other stages, with a genome-wide Ts/Tv ratio of 2.95. The maximum number of SNPs, 2853 (16.86%), was identified in chromosome 8, while the lowest, 1126 (6.65%), was identified in chromosome 7. The maximum and minimum numbers of InDels were located on chromosome 1 and 7, with 834 (13.38%) and 519 (8.33%), respectively. Annotation showed that highest numbers of exonic and intergenic SNPs were present at the late adult stage, whereas the maximum number of InDels was found at the larval stage. On the basis of gene function, 47 gene variations were screened and 23 candidate genes were identified in associations with lac production. Concluding work will enhance knowledge on molecular markers to facilitate an increase in lac production in K. lacca as well as other lac insects.

Toward Individualized Prediction of Response to Methotrexate in Early Rheumatoid Arthritis: A Pharmacogenomics-Driven Machine Learning Approach.

To test the ability of machine learning (ML) approaches with clinical and genomic biomarkers to predict methotrexate treatment response in patients with early rheumatoid arthritis (RA). Demographic, clinical, and genomic data from 643 patients of European ancestry with early RA (mean age 54 years; 70% female) subdivided into a training (n = 336) and validation cohort (n = 307) were used. The genomic data comprised 160 single-nucleotide polymorphisms (SNPs) previously associated with RA or methotrexate metabolism. Response to methotrexate monotherapy was defined as good or moderate by the European Alliance of Associations for Rheumatology (EULAR) response criteria at the 3-month follow-up. Supervised ML methods were trained with 5 repeats and 10-fold cross-validation using the training cohort. Prediction performance was validated in the independent validation cohort. Supervised ML methods combining age, sex, smoking, rheumatoid factor, baseline Disease Activity Score in 28 joints (DAS28) scores and 160 SNPs predicted EULAR response at 3 months with the area under the receiver operating curve of 0.84 (P = 0.05) in the training cohort and achieved a prediction accuracy of 76% (P = 0.05) in the validation cohort (sensitivity 72%, specificity 77%). Intergenic SNPs rs12446816, rs13385025, rs113798271, and ATIC (rs2372536) had variable importance above 60.0 and along with baseline DAS28 scores were among the top predictors of methotrexate response. Pharmacogenomic biomarkers combined with baseline DAS28 scores can be useful in predicting response to methotrexate in patients with early RA. Applying ML to predict treatment response holds promise for guiding effective RA treatment choices, including timely escalation of RA therapies.

The association of vascular endothelial growth factor related SNPs and circulating iron levels might depend on body mass index.

Vascular Endothelial Growth Factor (VEGF) is an essential regulator of vascular biology. In addition to the well-established role in angiogenesis, circulating VEGF levels were found elevated in severely anemic patients, pointing out that anemia might affect the progression of angiogenesis in malignant and benign diseases through the alteration of VEGF levels. Ten single nucleotide polymorphisms (SNPs) in VEGFA and other loci were shown to explain more than 50% of its circulating levels. This study investigated the association of those ten VEGF-related SNPs with serum iron levels in a general Lebanese population free of chronic diseases (N = 460). We found that the rs10738760 and the body mass index (BMI) were associated with decreased Iron levels (p = 0.002, and p < 0.001, respectively). When taken together, both variables, rs10738760 and BMI, interacted to reduce iron levels (p < 0.001). According to obesity status, the stratification revealed that the effect of rs10738760 was more pronounced in obese than non-obese individuals (p = 0.025).Conclusion: The intergenic SNP rs10738760 is associated with circulating iron levels, and this association depends on BMI status.Although of interest, these results need replication in larger populations from different ancestries.

Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study

BackgroundGenome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in three-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically associating domains (TADs) and their borders.ResultsFor each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e., the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that localization of risk loci in TAD borders differs between cancers and non-cancer diseases. Furthermore, different TAD border enrichments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk.ConclusionsOur results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with an effect on an individual gene, the other acting in interplay with 3D genome organization.

SNP characteristics and validation success in genome wide association studies.

Genome wide association studies (GWASs) have identified tens of thousands of single nucleotide polymorphisms (SNPs) associated with human diseases and characteristics. A significant fraction of GWAS findings can be false positives. The gold standard for true positives is an independent validation. The goal of this study was to identify SNP features associated with validation success. Summary statistics from the Catalog of Published GWASs were used in the analysis. Since our goal was an analysis of reproducibility, we focused on the diseases/phenotypes targeted by at least 10 GWASs. GWASs were arranged in discovery-validation pairs based on the time of publication, with the discovery GWAS published before validation. We used four definitions of the validation success that differ by stringency. Associations of SNP features with validation success were consistent across the definitions. The strongest predictor of SNP validation was the level of statistical significance in the discovery GWAS. The magnitude of the effect size was associated with validation success in a non-linear manner. SNPs with risk allele frequencies in the range 30-70% showed a higher validation success rate compared to rarer or more common SNPs. Missense, 5'UTR, stop gained, and SNPs located in transcription factor binding sites had a higher validation success rate compared to intergenic, intronic and synonymous SNPs. There was a positive association between validation success and the level of evolutionary conservation of the sites. In addition, validation success was higher when discovery and validation GWASs targeted the same ethnicity. All predictors of validation success remained significant in a multivariate logistic regression model indicating their independent contribution. To conclude, we identified SNP features predicting validation success of GWAS hits. These features can be used to select SNPs for validation and downstream functional studies.

Phenotypic effect of a single nucleotide polymorphism on SSC7 on fetal outcomes in PRRSV-2 infected gilts

Porcine reproductive and respiratory syndrome (PRRS) is one of the most common viral diseases affecting the global pork industry, causing significant economic loss in breeding herds and growing pigs. Control is challenging and genomic interventions can potentially yield alternative strategies to control PRRS virus (PRRSV) infection. We previously conducted a genome-wide association study to broaden our understanding of host genetics of fetal responses following maternal PRRSV infection and found that an intergenic single nucleotide polymorphism (SNP) near the DIO2 gene encoding the type II iodothyronine deiodinase, was significantly associated with fetal viability in response to maternal PRRSV infection. To determine the potential effect of this SNP on fetal outcomes including fetal viability, survival, growth and developmental characteristics in an independent pregnant gilt challenge model, we produced balanced homozygous fetal populations comprised of either the SNP's A or B allele. We assessed fetal viral loads in placenta, serum, and thymus, serum thyroid hormone levels, and growth and bone development by genotype at the SNP site. Unexpectedly, the BB genotype was not associated with greater odds ratio of fetal viability but was significantly related to reduced serum T4 level and increased area of the proximal humeral secondary ossification center (PHOC). To our knowledge, this is the first report of the variation in the genomic region influencing fetal T4 level and PHOC area in response to PRRSV infection. These results might implicate a functional effect of the genomic region on fetal thyroid hormone metabolism, which is partly involved in fetal bone biology during maternal PRRSV infection.

Mitochondrial and nuclear diversity of colonies of varying origins: contrasting patterns inferred from the intergenic tRNAleu-cox2 region and immune SNPs

In this study, we gathered sequence data from the tRNAleu-cox2 intergenic mitochondrial (mtDNA) region concurrently with single nucleotide polymorphism (SNP) data from 91 loci of nuclear DNA (ncDNA). The data was obtained from 156 colonies sampled in six apiaries from four countries. The full dataset was analysed and discussed for genetic patterns with a focus on cytonuclear diversity and admixture levels.

Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study

Naltrexone can aid in reducing alcohol consumption, while acamprosate supports abstinence; however, not all patients with alcohol use disorder (AUD) benefit from these treatments. Here we present the first genome-wide association study of AUD treatment outcomes based on data from the COMBINE and PREDICT studies of acamprosate and naltrexone, and the Mayo Clinic CITA study of acamprosate. Primary analyses focused on treatment outcomes regardless of pharmacological intervention and were followed by drug-stratified analyses to identify treatment-specific pharmacogenomic predictors of acamprosate and naltrexone response. Treatment outcomes were defined as: (1) time until relapse to any drinking (TR) and (2) time until relapse to heavy drinking (THR; ≥ 5 drinks for men, ≥4 drinks for women in a day), during the first 3 months of treatment. Analyses were performed within each dataset, followed by meta-analysis across the studies (N = 1083 European ancestry participants). Single nucleotide polymorphisms (SNPs) in the BRE gene were associated with THR (min p = 1.6E−8) in the entire sample, while two intergenic SNPs were associated with medication-specific outcomes (naltrexone THR: rs12749274, p = 3.9E−8; acamprosate TR: rs77583603, p = 3.1E−9). The top association signal for TR (p = 7.7E−8) and second strongest signal in the THR (p = 6.1E−8) analysis of naltrexone-treated patients maps to PTPRD, a gene previously implicated in addiction phenotypes in human and animal studies. Leave-one-out polygenic risk score analyses showed significant associations with TR (p = 3.7E−4) and THR (p = 2.6E−4). This study provides the first evidence of a polygenic effect on AUD treatment response, and identifies genetic variants associated with potentially medication-specific effects on AUD treatment response.

Imputation and Reanalysis of ExomeChip Data Identifies Novel, Conditional and Joint Genetic Effects on Parkinson's Disease Risk.

Given that improved imputation software and high-coverage whole genome sequence (WGS)-based haplotype reference panels now enable inexpensive approximation of WGS genotype data, we hypothesised that WGS-based imputation and analysis of existing ExomeChip-based genome-wide association (GWA) data will identify novel intronic and intergenic single nucleotide polymorphism (SNP) effects associated with complex disease risk. In this study, we reanalysed a Parkinson’s disease (PD) dataset comprising 5540 cases and 5862 controls genotyped using the ExomeChip-based NeuroX array. After genotype imputation and extensive quality control, GWA analysis was performed using PLINK and a recently developed machine learning approach (GenEpi), to identify novel, conditional and joint genetic effects associated with PD. In addition to improved validation of previously reported loci, we identified five novel genome-wide significant loci associated with PD: three (rs137887044, rs78837976 and rs117672332) with 0.01 < MAF < 0.05, and two (rs187989831 and rs12100172) with MAF < 0.01. Conditional analysis within genome-wide significant loci revealed four loci (p < 1 × 10−5) with multiple independent risk variants, while GenEpi analysis identified SNP–SNP interactions in seven genes. In addition to identifying novel risk loci for PD, these results demonstrate that WGS-based imputation and analysis of existing exome genotype data can identify novel intronic and intergenic SNP effects associated with complex disease risk.

Genetic and epigenetic interplay fine-tunes expression of TGFB1, encoding TGF-Β1, contributing to osteoarthritis risk

Genetic and epigenetic interplay fine-tunes expression of TGFB1, encoding TGF-Β1, contributing to osteoarthritis risk

Two-stage genome-wide association study of chronic rhinosinusitis and disease subphenotypes highlights mucosal immunity contributing to risk.

Two-stage genome-wide association study of chronic rhinosinusitis and disease subphenotypes highlights mucosal immunity contributing to risk.