Case-control Genome-wide Association Studies Research Articles

A Genome-Wide Association Study (GWAS) of Takotsubo syndrome

Abstract Background Takotsubo syndrome (TS) is an acute cardiac condition of unknown etiology characterized by transient regional systolic dysfunction of the left and/or right ventricle. Several studies have suggested the importance of genetics; however, studies are limited and have presented conflicting results. Purpose To identify potential genetic risk variants associated with TS. Methods A case-control GWAS in three steps; I) A discovery study with Swedish takotsubo cases (n=260) and age- and sex-matched controls without heart disease from the UK Biobank (n=3034), II) A replication study of Swedish takotsubo cases (n=250) and sex- and age-matched Swedish controls without myocardial infarction from the Swedish coronary angiography and angioplasty register (n=229), III) A Meta-analysis of study I-II with extended controls from the UK-biobank (n=5161). Genotyping was performed using the Axiom® UK Biobank Genotyping Array including 820 000 single nucleotide polymorphisms (SNPs). After applying filters and QC control around 480 000 SNPs remained with a Bonferroni corrected p-value 1*10^-7, minor allele frequency (MAF 1.5-2%), Hardy-Weinberg (HWE) 10^-6. QC, filtering and analysis were performed in PLINK 1.9 and R v 4.0. Results In the discovery (I) 1490 SNP:s fulfilled a significance level of <10^-4, of which 36 SNP:s replicated (II) with a significance level of <10^-2, 11 reached a significance level of 10^-7 in the meta-analysis (III). One of the 36 SNP:s, rs1614887, replicated (II) with a significance level of 10^-3. This SNP is an intron variant in the butyrophilin subfamily 2 member A2 gene, a glycoprotein receptor involved in lipid, fatty-acid and sterol metabolism highly expressed in the heart. Of the 11 SNP:s with a significance level of 10^-7 in the meta-analysis (III) several risk variants were associated with psoriasis. Conclusions This is the largest GWAS of takotsubo syndrome performed so far, identifying one candidate gene and several potential risk variants. Further research of genetic risk variants in TS is warranted.

A genome-wide association study of adults with community-acquired pneumonia

BackgroundCommunity-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS).MethodsWe performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted.ResultsSix independent sentinel variants reached the genome-wide significance (p < 5 × 10-8), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles.ConclusionsWe completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.

Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke.

Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking. A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data. Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P=4.34×10-8). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings. We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice.

A GWAS of ACE Inhibitor-Induced Angioedema in a South African Population.

Angiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population. The GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls). No SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10-06). Some of these SNPs were found to be located close to the genes PRKCQ and RIMS1, previously linked with drug-induced angioedema, and also close to the CSMD1 gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs. Our results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.

Retrospective Single Nucleotide Polymorphism Analysis of Host Resistance and Susceptibility to Ovine Johne's Disease Using Restored FFPE DNA.

Johne's disease (JD), also known as paratuberculosis, is a chronic, untreatable gastroenteritis of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. Evidence for host genetic resistance to disease progression exists, although it is limited due to the extended incubation period (years) and diagnostic challenges. To overcome this, previously restored formalin-fixed paraffin embedded tissue (FFPE) DNA from archived FFPE tissue cassettes was utilized for a novel retrospective case-control genome-wide association study (GWAS) on ovine JD. Samples from known MAP-infected flocks with ante- and postmortem diagnostic data were used. Cases (N = 9) had evidence of tissue infection, compared to controls (N = 25) without evidence of tissue infection despite positive antemortem diagnostics. A genome-wide efficient mixed model analysis (GEMMA) to conduct a GWAS using restored FFPE DNA SNP results from the Illumina Ovine SNP50 Bead Chip, identified 10 SNPs reaching genome-wide significance of p < 1 × 10-6 on chromosomes 1, 3, 4, 24, and 26. Pathway analysis using PANTHER and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was completed on 45 genes found within 1 Mb of significant SNPs. Our work provides a framework for the novel use of archived FFPE tissues for animal genetic studies in complex diseases and further evidence for a genetic association in JD.

Genetic insights into drug targets for sporadic Creutzfeldt-Jakob disease: Integrative multi-omics analysis

ObjectiveSporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive neurodegenerative disorder with no effective therapeutic interventions. We aimed to identify potential genetically-supported drug targets for sCJD by integrating multi-omics data. MethodsMulti-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues. Outcome data was from a case-control genome-wide association study, which included 4110 sCJD patients and 13,569 controls. Further investigations encompassed druggability, potential side effects, and associated biological pathways of the identified targets. ResultsIntegrative multi-omics analysis identified 23 potential therapeutic targets for sCJD, with five targets (STX6, XYLT2, PDIA4, FUCA2, KIAA1614) having higher levels of evidence. One target (XYLT2) shows promise for repurposing, two targets (XYLT2, PDIA4) are druggable, and three (STX6, KIAA1614, and FUCA2) targets represent potential future breakthrough points. The expression level of STX6 and XYLT2 in neurons and oligodendrocytes was closely associated with an increased risk of sCJD. Brain regions with high expression of STX6 or causal links to sCJD were often those areas commonly affected by sCJD. ConclusionsOur study identified five potential therapeutic targets for sCJD. Further investigations are warranted to elucidate the mechanisms underlying the new targets for developing disease therapies or initiate clinical trials.

Genetic factors contributing to the development of inguinal hernias – a narrative review

Introduction and aim. Inguinal hernias are one of the major disorders in the field of general and visceral surgery and can be viewed as multifactorial diseases. Although the molecular mechanism that led to predistortion to inguinal herniation still remain unclear, is well known that defects leading to improper closure of the inguinal canal during fetal development and mechanisms contributing to weaker muscles of the abdominal wall can greatly increase the risk of developing the latter disease. Material and methods. A literature search was performed in all major electronic databases using keywords and Boolean operators to retrieve all available literature related to the topic. Due to the narrative nature of the review, there were no specific inclusion and exclusion criteria. Analysis of the literature. Genetic factors, undoubtedly, can interfere with these mechanisms and therefore play major role in developing hernias. To this end, the present narrative review provides an overview of genes with altered expression and genetic polymorphisms associated with inguinal herniation. Moreover, the results of genome-wide association studies (GWAS) exploring susceptible genetic loci associated with the disease have been reported. Conclusion. Nevertheless, more case-control studies and GWAS need to be conducted in different ethnic populations so as to provide better insights into the topic.

RNF213 Variants, Vasospastic Angina, and Risk of Fatal Myocardial Infarction

Vasospastic angina (VSA) is vasospasm of the coronary artery and is particularly prevalent in East Asian populations. However, the specific genetic architecture for VSA at genome-wide levels is not fully understood. To identify genetic factors associated with VSA. This was a case-control genome-wide association study of VSA. Data from Biobank Japan (BBJ; enrolled patients from 2002-2008 and 2013-2018) were used, and controls without coronary artery disease (CAD) were enrolled. Patients from the BBJ were genotyped using arrays or a set of arrays. Patients recruited between 2002 and 2005 were classified within the first dataset, and those recruited between 2006 and 2008 were classified within the second dataset. To replicate the genome-wide association study in the first and second datasets, VSA cases and control samples from the latest patients in the BBJ recruited between 2013 and 2018 were analyzed in a third dataset. Single-nucleotide variants associated with VSA. Cases with VSA and controls without CAD. A total of 5720 cases (mean [SD] age, 67 [10] years; 3672 male [64.2%]) and 153 864 controls (mean [SD] age, 62 [15] years; 77 362 male [50.3%]) in 3 datasets were included in this study. The variants at the RNF213 locus showed the strongest association with VSA across the 3 datasets (odds ratio [OR], 2.34; 95% CI, 1.99-2.74; P = 4.4 × 10-25). Additionally, rs112735431, an Asian-specific rare deleterious variant (p.Arg4810Lys) experimentally shown to be associated with reduced angiogenesis and a well-known causal risk for Moyamoya disease was the most promising candidate for a causal variant explaining the association. The effect size of rs112735431 on VSA was distinct from that of other CADs. Furthermore, homozygous carriers of rs112735431 showed an association with VSA characterized by a large effect estimate (OR, 18.34; 95% CI, 5.15-65.22; P = 7.0 × 10-6), deviating from the additive model (OR, 4.35; 95% CI, 1.18-16.05; P = .03). Stratified analyses revealed that rs112735431 exhibited a stronger association in males (χ21 = 7.24; P = .007) and a younger age group (OR, 3.06; 95% CI, 2.24-4.19), corresponding to the epidemiologic features of VSA. In the registry, carriers without CAD of the risk allele rs112735431 had a strikingly high mortality rate due to acute myocardial infarction during the follow-up period (hazard ratio, 2.71; 95% CI, 1.57-4.65; P = 3.3 × 10-4). As previously reported, a possible overlap between VSA and Moyamoya disease was not found. Results of this study suggest that vascular cell dysfunction mediated by variants in the RNF213 locus may promote coronary vasospasm, and the presence of the risk allele could serve as a predictive factor for the prognosis.

FastBiCmrMLM: a fast and powerful compressed variance component mixed logistic model for big genomic case-control genome-wide association study.

Large sample datasets have been regarded as the primary basis for innovative discoveries and the solution to missing heritability in genome-wide association studies. However, their computational complexity cannot consider all comprehensive effects and all polygenic backgrounds, which reduces the effectiveness of large datasets. To address these challenges, we included all effects and polygenic backgrounds in a mixed logistic model for binary traits and compressed four variance components into two. The compressed model combined three computational algorithms to develop an innovative method, called FastBiCmrMLM, for large data analysis. These algorithms were tailored to sample size, computational speed, and reduced memory requirements. To mine additional genes, linkage disequilibrium markers were replaced by bin-based haplotypes, which are analyzed by FastBiCmrMLM, named FastBiCmrMLM-Hap. Simulation studies highlighted the superiority of FastBiCmrMLM over GMMAT, SAIGE and fastGWA-GLMM in identifying dominant, small α (allele substitution effect), and rare variants. In the UK Biobank-scale dataset, we demonstrated that FastBiCmrMLM could detect variants as small as 0.03% and with α ≈ 0. In re-analyses of seven diseases in the WTCCC datasets, 29 candidate genes, with both functional and TWAS evidence, around 36 variants identified only by the new methods, strongly validated the new methods. These methods offer a new way to decipher the genetic architecture of binary traits and address the challenges outlined above.

Genome-wide association study for the level of prolificacy in Cameroon’s native goat

ABSTRACT Income from goats highly depends on prolificacy, which is difficult to improve by traditional breeding methods. The study aimed to identify SNP markers for prolificacy, using a case–control genome-wide association study (GWAS) on 111 genotyped Cameroon native goat (CNG) does, based on the 50 K single nucleotide polymorphism (SNP) chip panel. None of the top SNPs reached the significant p-value of 5 × 10−8. The highest p-value was 0.0009. Despite the number of cases being about a quarter of the number of controls, the highest allele frequency of some of the top 20 variants in the cases was indicative of their potential role in the trait. These top variants included the following 15: rs268285661, rs268235169, rs268236449, rs268235135, rs268240394 in Sphingosine-1-phosphate phosphatase 2 (SGPP2) gene, rs268283635 in Solute carrier family 24 member 2 (SLC24A2) gene, rs268251678 in Androgen-induced gene 1 (AIG1) gene, rs268267018, rs268239617, rs268281364, rs268273029, rs268286941, rs268236144, rs268233233 in CEP126 gene and rs268278159, respectively. Our findings indicate that GWAS enable the identification of some loci within genes, with known biological functions and pathways in human being and mice animal model but far-ranging to what was previously hypothesized and tested in goat.

Genetics may affect the risk of undergoing surgery for rhizarthrosis.

Osteoarthritis is a prevalent and severe disease. Involvement of the trapeziometacarpal joint is common and can lead to both pain and disability. Genetics are known to affect the risk of osteoarthritis, but it remains unclear how genetics affect disease trajectories. In this study, we investigated whether the genetic associations of trapeziometacarpal osteoarthritis (rhizarthrosis) vary with the need for surgical treatment. The study was conducted as a case-control genome-wide association study using individuals from the Copenhagen Hospital Biobank pain and degenerative musculoskeletal disease study and the Danish Blood Donor Study (N = 208,342). We identified patients diagnosed with rhizarthrosis and grouped them by treatment status, resulting in two case groups: surgical (N = 1083) and nonsurgical (N = 1888). The case groups were tested against osteoarthritis-free controls in two genome-wide association studies. We then compared variants suggestive of association (p < 10-6) in either of these analyses directly between the treatment groups (surgical vs. nonsurgical rhizarthrosis). We identified 10 variants suggestive of association with either surgical (seven variants) or nonsurgical (three variants) rhizarthrosis. None of the variants reached nominal significance in the opposite treatment group (p ≥ 0.14), and all 10 variants were significantly different between the treatment groups at a false discovery rate of 5%. These results suggest possible differences in the genetic associations of rhizarthrosis depending on surgical treatment. Clinical significance: Uncovering genetic differences between clinically distinct patient groups can reveal biological determinants of disease trajectories.

Genome-wide association study suggests genetic candidate loci of insulin dysregulation in Finnhorses

Equine metabolic syndrome (EMS) is a common welfare problem in horses worldwide. It is characterized by insulin dysregulation (ID), predisposition to laminitis and often obesity. EMS is multifactorial by nature, with both the environment and genetics contributing to the phenotype. Environmental factors, such as feeding and exercise, can be controlled, thus forming the basis for treatment and prevention. Genetic factors, by contrast, are less well-known and not easily controllable. The aim of this study was to identify potential genetic loci influencing ID/EMS in Finnhorses. A single-breed (Finnhorse) case-control genome-wide association study (GWAS) of ID was conducted with controls that included age-appropriate non-ID horses. ID status was determined with an oral sugar test (OST) for fasted horses. Seventy-one Finnhorses participated (n = 34 ID, n = 37 control). DNA samples (hair roots) were genotyped for 65 157 single-nucleotide polymorphisms (SNPs) with the Illumina Equine SNP70 BeadChip, and these data were analysed for association and FST outliers with genomic tools. P-values that exceeded the suggestive threshold (P = 1.00 ×10−5) were found in SNP BIEC2_383954 (P = 3.45 ×10−6) in chromosome 17 and SNP BIEC2_312374 (P = 1.89 ×10−5) in chromosome 15. Hierarchical and Bayesian FST outlier tests also detected these SNPs. Potential candidate genes associated with the ID close to SNP BIEC2_383954, with functions in carbohydrate metabolism, were Arginine and Glutamate Rich 1 (ARGLU1) and Ephrin-B2 (EFNB2).

Genome-wide case-control association study identifies a locus connecting NRF2-ARE regulation and selenium deficiency

Genome-wide case-control association study identifies a locus connecting NRF2-ARE regulation and selenium deficiency

Angular limb deformity associated with TSPAN18, NRG3 and NOVA2 in Rambouillet rams

Angular limb deformity (ALD) affects many species of livestock and companion animals. The mechanisms of ALD development are not well understood, but previous research suggests the involvement of genetic risk factors. A case-control genome-wide association study (GWAS) was conducted with 40 ALD-affected and 302 unaffected Rambouillet rams and 40,945 single nucleotide polymorphisms (SNPs). Forelimbs of 6 ALD-affected rams were examined and diagnosed with osteochondrosis. Genome-wide or chromosome-wide significant SNPs were positioned exonic, intronic or within the 3′UTR of genes TSPAN18, NRG3 and NOVA2, respectively. These genes have previously described roles related to angiogenesis and osteoblast, osteoclast and chondrocyte proliferation and differentiation, which suggests the possibility for their involvement in the pathogenesis of osteochondrosis. Functional consequences of SNPs were evaluated through transcription factor binding site analysis, which predicted binding sites for transcription factors of known importance to bone growth, including SOX6, SOX9 and RUNX2. The identification of genetic risk factors for ALD may help to improve animal welfare and production in Rambouillet, a breed known to be at risk for ALD development. This study proposes genes TSPAN18, NRG3 and NOVA2 as targets for further research towards understanding the etiology of ALD in Rambouillet sheep.

Lymphoma in Border Collies: Genome-Wide Association and Pedigree Analysis.

There has been considerable interest in studying cancer in dogs and its potential as a model system for humans. One area of research has been the search for genetic risk variants in canine lymphoma, which is amongst the most common canine cancers. Previous studies have focused on a limited number of breeds, but none have included Border Collies. The aims of this study were to identify relationships between Border Collie lymphoma cases through an extensive pedigree investigation and to utilise relationship information to conduct genome-wide association study (GWAS) analyses to identify risk regions associated with lymphoma. The expanded pedigree analysis included 83,000 Border Collies, with 71 identified lymphoma cases. The analysis identified affected close relatives, and a common ancestor was identified for 54 cases. For the genomic study, a GWAS was designed to incorporate lymphoma cases, putative "carriers", and controls. A case-control GWAS was also conducted as a comparison. Both analyses showed significant SNPs in regions on chromosomes 18 and 27. Putative top candidate genes from these regions included DLA-79, WNT10B, LMBR1L, KMT2D, and CCNT1.

ADuLT: An efficient and robust time-to-event GWAS

Proportional hazards models have been proposed to analyse time-to-event phenotypes in genome-wide association studies (GWAS). However, little is known about the ability of proportional hazards models to identify genetic associations under different generative models and when ascertainment is present. Here we propose the age-dependent liability threshold (ADuLT) model as an alternative to a Cox regression based GWAS, here represented by SPACox. We compare ADuLT, SPACox, and standard case-control GWAS in simulations under two generative models and with varying degrees of ascertainment as well as in the iPSYCH cohort. We find Cox regression GWAS to be underpowered when cases are strongly ascertained (cases are oversampled by a factor 5), regardless of the generative model used. ADuLT is robust to ascertainment in all simulated scenarios. Then, we analyse four psychiatric disorders in iPSYCH, ADHD, Autism, Depression, and Schizophrenia, with a strong case-ascertainment. Across these psychiatric disorders, ADuLT identifies 20 independent genome-wide significant associations, case-control GWAS finds 17, and SPACox finds 8, which is consistent with simulation results. As more genetic data are being linked to electronic health records, robust GWAS methods that can make use of age-of-onset information will help increase power in analyses for common health outcomes.

Genome-wide association study of abnormal elevation of ALT in patients exposed to atabecestat

BackgroundAtabecestat, a potent brain penetrable BACE1 inhibitor that reduces CSF amyloid beta (Aβ), was developed as an oral treatment for Alzheimer’s disease (AD). Elevated liver enzyme adverse events were reported in three studies although only one case met Hy’s law criteria to predict serious hepatotoxicity.MethodWe performed a case-control genome-wide association study (GWAS) to identify genetic risk variants associated with liver enzyme elevation using 42 cases with alanine transaminase (ALT) above three times the upper limit of normal (ULN) and 141 controls below ULN. Additionally, we performed a GWAS using continuous maximal ALT/ULN (expressed as times the ULN) upon exposure to atabecestat as the outcome measure (n = 285).ResultsNo variant passed the genome-wide significance threshold (p = 5 × 10− 8) in the case-control GWAS. We identified suggestive association signals in genes (NLRP1, SCIMP, and C1QBP) implicated in the inflammatory processes. Among the genes implicated by position mapping using variants suggestively associated (p < 1 × 10− 5) with ALT elevation case-control status, gene sets involved in innate immune response (adjusted p-value = 0.05) and regulation of cytokine production (adjusted p-value = 0.04) were enriched. One genomic region in the intronic region of GABRG3 passed the genome-wide significance threshold in the continuous max(ALT/ULN) GWAS, and this variant was nominally associated with ALT elevation case status (p = 0.009).ConclusionThe suggestive GWAS signals in the case-control GWAS analysis suggest the potential role of inflammation in atabecestat-induced liver enzyme elevation.

Investigating the Genetic Background of Spastic Syndrome in North American Holstein Cattle Based on Heritability, Genome-Wide Association, and Functional Genomic Analyses.

Spastic syndrome is a chronic, progressive disorder of adult cattle characterized by episodes of sudden involuntary muscle contractions or spasms of the extensor and abductor muscles of one or both hind limbs. In this study, a case-control genome-wide association study (GWAS) was performed on an adult Holstein cattle cohort. Based on the 50 K and high-density (HD) SNP panel GWAS, we identified 98 and 522 SNPs, respectively. The most significant genomic regions identified are located on BTA9 at approximately 87 megabase pairs (Mb) and BTA7 between 1 and 20 Mb. Functional analyses of significant SNPs identified genes associated with muscle contraction, neuron growth or regulation, and calcium or sodium ion movement. Two candidate genes (FIG4 and FYN) were identified. FIG4 is ubiquitously expressed in skeletal muscle and FYN is involved with processes such as forebrain development, neurogenesis, locomotion, neurogenesis, synapse development, neuron migration, and the positive regulation of neuron projection development. The CACNA1A gene, which codes for a calcium channel subunit protein in the calcium signaling pathway, seems the most compelling candidate gene, as many calcium ion channel disorders are non-degenerative, and produce spastic phenotypes. These results suggest that spastic syndrome is of polygenic inheritance, with important genomic areas of interest on BTA7 and BTA9.

Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. To identify the genes and pathways associated with idiopathic MFC. This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.

Automatic block-wise genotype-phenotype association detection based on hidden Markov model

BackgroundFor detecting genotype-phenotype association from case–control single nucleotide polymorphism (SNP) data, one class of methods relies on testing each genomic variant site individually. However, this approach ignores the tendency for associated variant sites to be spatially clustered instead of uniformly distributed along the genome. Therefore, a more recent class of methods looks for blocks of influential variant sites. Unfortunately, existing such methods either assume prior knowledge of the blocks, or rely on ad hoc moving windows. A principled method is needed to automatically detect genomic variant blocks which are associated with the phenotype.ResultsIn this paper, we introduce an automatic block-wise Genome-Wide Association Study (GWAS) method based on Hidden Markov model. Using case–control SNP data as input, our method detects the number of blocks associated with the phenotype and the locations of the blocks. Correspondingly, the minor allele of each variate site will be classified as having negative influence, no influence or positive influence on the phenotype. We evaluated our method using both datasets simulated from our model and datasets from a block model different from ours, and compared the performance with other methods. These included both simple methods based on the Fisher’s exact test, applied site-by-site, as well as more complex methods built into the recent Zoom-Focus Algorithm. Across all simulations, our method consistently outperformed the comparisons.ConclusionsWith its demonstrated better performance, we expect our algorithm for detecting influential variant sites may help find more accurate signals across a wide range of case–control GWAS.