The same ELA class II risk factors confer equine insect bite hypersensitivity in two distinct populations

Insect bite hypersensitivity (IBH) is a chronic allergic dermatitis common in horses. Affected horses mainly react against antigens present in the saliva from the biting midges, Culicoides ssp, and occasionally black flies, Simulium ssp. Because of this insect dependency, the disease is clearly seasonal and prevalence varies between geographical locations. For two distinct horse breeds, we genotyped four microsatellite markers positioned within the MHC class II region and sequenced the highly polymorphic exons two from DRA and DRB3, respectively. Initially, 94 IBH-affected and 93 unaffected Swedish born Icelandic horses were tested for genetic association. These horses had previously been genotyped on the Illumina Equine SNP50 BeadChip, which made it possible to ensure that our study did not suffer from the effects of stratification. The second population consisted of 106 unaffected and 80 IBH-affected Exmoor ponies. We show that variants in the MHC class II region are associated with disease susceptibility (p (raw)?=?2.34?×?10(-5)), with the same allele (COR112:274) associated in two separate populations. In addition, we combined microsatellite and sequencing data in order to investigate the pattern of homozygosity and show that homozygosity across the entire MHC class II region is associated with a higher risk of developing IBH (p?=?0.0013). To our knowledge this is the first time in any atopic dermatitis suffering species, including man, where the same risk allele has been identified in two distinct populations.     

Genome‐wide association study of insect bite hypersensitivity in Dutch Shetland pony mares

Insect bite hypersensitivity (IBH) is the most common allergic disease present in horses worldwide. It has been shown that IBH is under genetic control, but the knowledge of associated genes is limited. We conducted a genome‐wide association study to identify and quantify genomic regions contributing to IBH in the Dutch Shetland pony population. A total of 97 cases and 91 controls were selected and matched on withers height, coat colour and pedigree to minimise the population stratification. A blood sample was collected from participating Shetland pony mares, their IBH phenotype was scored and the owner filled in a questionnaire. A total of 40 021 single‐nucleotide polymorphisms (SNPs) were fitted in a univariable logistic model fitting an additive effect. Analysis revealed no effects of population stratification. Significant associations with IBH were detected for 24 SNPs on 12 chromosomes [?log₁₀(P‐value) > 2.5]. Odds ratios of allele substitution effects of the unfavourable allele were between 1.94 and 5.95. The most significant SNP was found on chromosome 27, with an odds ratio of 2.31 and with an allele frequency of the unfavourable allele of 0.72 in cases and 0.53 in controls. Genome‐wide association studies on additional horse populations are desired to validate the identified associations, to identify the genes involved in IBH and to develop genomic tools to decrease IBH prevalence.     

A prospective study on insect bite hypersensitivity in horses exported from Iceland into Switzerland

Background

Insect bite hypersensitivity (IBH) is an IgE-mediated dermatitis caused by bites of Culicoides spp., which occurs frequently in horses imported from Iceland to continental Europe. IBH does not occur in Iceland because Culicoides species that bite horses are not present. However, Simulium vittatum (S. vittatum) are found in Iceland. In Europe, blood basophils from IBH-affected horses release significantly more sulfidoleukotrienes (sLT) than those from healthy controls after in vitro stimulation with Culicoides nubeculosus (C. nubeculosus) and S. vittatum. Aims of the study were: (I) using the sLT release assay, to test if horses living in Iceland were sensitized to S. vittatum and (II) to determine in a longitudinal study in horses imported from Iceland to Switzerland whether the sLT release assay would allow to predict which horses would develop IBH.

Results

Horses in Iceland, even when living in high S. vittatum areas, were usually not sensitized to S. vittatum or C. nubeculosus. Incidence of IBH in the 145 horses from the longitudinal study was 51% and mean time until IBH developed was 2.5?±?1 year. Before import and after the first summer following import, there were no significant differences in sLT release between the endpoint healthy (H) and IBH groups. After the 2nd summer, when the number of clinically affected horses increased in the endpoint IBH group, a significantly higher sLT release after stimulation with C. nubeculosus but not with S. vittatum was observed. After the 3rd and 4th summer, the endpoint IBH group had a significantly higher sLT release with C. nubeculosus and S. vittatum than the endpoint H group. Some of the horses that remained healthy became transiently positive in the sLT release assay upon stimulation of their peripheral blood leucocytes with C. nubeculosus.

Conclusions

Horses in Iceland are not sensitized to S. vittatum. In horses that develop IBH, sensitization to S. vittatum is secondary to sensitization to C. nubeculosus and probably a result of an immunological cross-reactivity. A sLT release assay cannot be used to predict which horses will develop IBH. A transient positive reaction in the sLT release assay observed in horses that remained healthy suggests that immunoregulatory mechanisms may control an initial sensitization of the healthy horses.

     

Genetic analysis of insect bite hypersensitivity (summer eczema) in Icelandic horses

There is a lack of knowledge about the genetic background of eczema due to insect bite hypersensitivity, also called summer eczema, in horses. The condition is known in several horse breeds and countries and it causes reduced welfare of the horse and economic losses to the owner. The aim of this study was to estimate genetic parameters for summer eczema in Swedish-born Icelandic horses. A questionnaire was sent to owners of horses sired by stallions with more than 50 offspring born in Sweden between 1991 and 2001. Variance components of summer eczema classified as healthy, mild, moderate or severe were estimated using the threshold methodology with sire models. In addition, summer eczema was analysed as a binary trait (healthy v. affected). The analyses included 1250 horses sired by 33 stallions. The prevalence of summer eczema was 8%, with a range of 0% to 30% in different paternal half-sib groups. Offspring of dams suffering from eczema had a higher risk of developing eczema. The heritability for severity of summer eczema was estimated at 0.3 (s.d. < 0.2) with a threshold sire model. In contrast to the age of the horse, different geographic areas and gender were significantly associated with severity of the eczema. We conclude that genetic selection could decrease the prevalence of summer eczema among Swedish-born Icelandic horses. The amount and quality of data are, however, crucial for the possibility to introduce a genetic evaluation of summer eczema. The symptoms should be classified in several classes according to severity, and this classification could be made by the horse owner.     

Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations

Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1×10⁻⁸) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (P _combined = 2.3×10⁻¹⁰, odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10⁻¹⁰, OR = 1.52, and DPB1*0901: P = 2.0×10⁻⁷, OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.     

Genome-wide association study of footrot in Texel sheep

Background

This is the first study based on a genome-wide association approach that investigates the links between ovine footrot scores and molecular polymorphisms in Texel sheep using the ovine 50 K SNP array (42 883 SNPs (single nucleotide polymorphisms) after quality control). Our aim was to identify molecular predictors of footrot resistance.

Methods

This study used data from animals selected from a footrot-phenotyped Texel sheep population of 2229 sheep with an average of 1.60 scoring records per animal. From these, a subset of 336 animals with extreme trait values for footrot was selected for genotyping based on their phenotypic records. De-regressed estimated breeding values (EBV) for footrot were used as pseudo-phenotypes in the genome-wide association analysis.

Results

Seven SNPs were significant on a chromosome-wise level but the association analysis did not reveal any genome-wise significant SNPs associated with footrot. Based on the current state of knowledge of the ovine genome, it is difficult to clearly link the function of the genes that contain these significant SNPs with a potential role in resistance/susceptibility to footrot. Linkage disequilibrium (LD) was analysed as one of the factors that influence the power of detecting QTL (quantitative trait loci). A mean LD of 0.20 (r² at a distance of 50 kb between two SNPs) in the population analysed was estimated. LD declined from 0.15 to 0.07 and to 0.04 at distances between two SNPs of 100, 1000 and 2000 kb, respectively.

Conclusions

Based on a relatively small number of genotyped animals, this study is a first step to search for genomic regions that are involved in resistance to footrot using the ovine 50 K SNP array. Seven SNPs were found to be significant on a chromosome-wise level. No major genome-wise significant QTL were identified.     

Genome-wide association study of schizophrenia in Japanese population

Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p = 0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology.     

Genome-wide association study of birth weight in sheep

Birth weight is the earliest available growth trait with considerable impacts on lamb survivability and growth performance traits. This study was conducted to perform a genome-wide association study of birth weight in a meat-type sheep. A total of 132 Lori-Bakhtiari sheep were selected based on estimated of breeding values (EBVs) for BW analyses. The selected animals were genotyped using Illumina Ovine SNP50 Bead Chip. After quality control, a total of 41 323 single-nucleotide polymorphisms (SNPs) and 130 sheep were used for subsequent analyses. Plink 1.90 beta software was used for the analyses. Seven SNPs on chromosomes 1, 16, 19 and 22 were detected based on genome-wide unadjusted P-values (P <10⁻⁶), which jointly accounted for 1.2% of total genetic variation. However, based on Bonferroni-adjusted P-values, only three SNPs on chromosome 1 had significant associations with EBVs for birth weight (P <0.05), which jointly explained 0.8% of total genetic variation. A total of seven genes were found in 50 kb intervals from the three significant SNPs on chromosome 1, but only three genes, including RAB6B (a member of RAS oncogene family), Tf serotransferrin and GIGYF2 (a GRB10 interacting GYF protein 2), could be considered as candidate genes for birth weight in future studies. The results of this study may facilitate potential use of the genes involving in growth and production traits for genetic improvement of productivity in sheep.     

Major histocompatibility complex and other allergy-related candidate genes associated with insect bite hypersensitivity in Icelandic horses

Insect bite hypersensitivity (IBH) is an allergic dermatitis of horses caused by bites of insects. IBH is a multifactorial disease with contribution of genetic and environmental factors. Candidate gene association analysis of IBH was performed in a group of 89 Icelandic horses all born in Iceland and imported to Europe. Horses were classified in IBH-affected and non-affected based on clinical signs and history of recurrent dermatitis, and on the results of an in vitro sulfidoleukotriene (sLT)-release assay with Culicoides nubeculosus and Simulium vittatum extract. Different genetic markers were tested for association with IBH by the Fisher’s exact test. The effect of the major histocompatibility complex (MHC) gene region was studied by genotyping five microsatellites spanning the MHC region (COR112, COR113, COR114, UM011 and UMN-JH34-2), and exon 2 polymorphisms of the class II Eqca-DRA gene. Associations with Eqca-DRA and COR113 were identified (p < 0.05). In addition, a panel of 20 single nucleotide polymorphisms (SNPs) in 17 candidate allergy-related genes was tested. During the initial screen, no marker from the panel was significantly (p < 0.05) associated with IBH. Five SNPs associated with IBH at p < 0.10 were therefore used for analysis of combined genotypes. Out of them, SNPs located in the genes coding for the CD14 receptor (CD14), interleukin 23 receptor (IL23R), thymic stromal lymphopoietin (TSLP) and transforming growth factor beta 3 (TGFB3) molecules were associated with IBH as parts of complex genotypes. These results are supported by similar associations and by expression data from different horse populations and from human studies.     

Genome-wide association study of relative telomere length

Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses'' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses'' Health Study and Women''s Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = −0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.     

Substance dependence low-density whole genome association study in two distinct American populations

Cocaine and opioid dependence are common, complex disorders with high heritability that commonly co-occur with other substance dependence disorders. Improved insight into the genetic basis of substance dependence would help elucidate its etiology and could inform its prevention and treatment. To generate new hypotheses about the genetics of substance dependence, we genotyped 5633 tagging single nucleotide polymorphism (SNP) markers in 1699 subjects from 339 African American (AA) families and 334 European American (EA) families ascertained through a sib pair meeting DSM-IV criteria for either cocaine or opioid dependence. The associations between genetic markers and five substance dependence traits (cocaine dependence, opioid dependence, cocaine-induced paranoia, alcohol dependence, and nicotine dependence) were assessed by family based association tests (FBAT). Results were ranked according to several criteria including statistical significance, concordance of results across population samples, and potential biological relevance of the implicated gene. The top-ranked result was an association of SNP rs1133503 in the MANEA gene with cocaine-induced paranoia (CIP). Our study provides an initial substance dependence trait-specific blueprint of associated regions for future candidate gene studies.     

Genome-wide association study identifies two major loci affecting calving ease and growth-related traits in cattle

Identifying quantitative trait loci (QTL) underlying complex, low-heritability traits is notoriously difficult. Prototypical for such traits, calving ease is an important breeding objective of cattle (Bos taurus)-improving programs. To identify QTL underlying calving ease, we performed a genome-wide association study using estimated breeding values (EBVs) as highly heritable phenotypes for paternal calving ease (pCE) and related traits. The massively structured study population consisted of 1800 bulls of the German Fleckvieh (FV) breed. Two pCE-associated regions on bovine chromosomes (BTA) 14 and 21 (P = 5.72 × 10(-15) and P = 2.27 × 10(-8), respectively) were identified using principal components analysis to correct for population stratification. The two most significantly associated SNPs explain 10% of the EBV variation. Since marker alleles with negative effect on pCE have positive effects on growth-related traits, the QTL may exert their effects on the birthing process through fetal growth traits. The QTL region on BTA14 corresponds to a human chromosome (HSA) region that is associated with growth characteristics. The HSA region corresponding to the BTA21 pCE QTL is maternally imprinted and involved in the Prader-Willi and Angelman syndromes. Resequencing of positional candidate genes on BTA14 revealed a highly significantly (P = 1.96 × 10(-14)) associated polymorphism ablating a polyadenylation signal of the gene encoding ribosomal protein S20 (RPS20). Our study demonstrates the leverage potential of EBVs in unraveling the genetic architecture of lowly heritable traits.     

Genome-wide association analyses reveal significant loci and strong candidate genes for growth and fatness traits in two pig populations

Background

Recently, genome-wide association studies (GWAS) have been reported on various pig traits. We performed a GWAS to analyze 22 traits related to growth and fatness on two pig populations: a White Duroc × Erhualian F₂ intercross population and a Chinese Sutai half-sib population.

Results

We identified 14 and 39 loci that displayed significant associations with growth and fatness traits at the genome-wide level and chromosome-wide level, respectively. The strongest association was between a 750 kb region on SSC7 (SSC for Sus scrofa) and backfat thickness at the first rib. This region had pleiotropic effects on both fatness and growth traits in F₂ animals and contained a promising candidate gene HMGA1 (high mobility group AT-hook 1). Unexpectedly, population genetic analysis revealed that the allele at this locus that reduces fatness and increases growth is derived from Chinese indigenous pigs and segregates in multiple Chinese breeds. The second strongest association was between the region around 82.85 Mb on SSC4 and average backfat thickness. PLAG1 (pleiomorphic adenoma gene 1), a gene under strong selection in European domestic pigs, is proximal to the top SNP and stands out as a strong candidate gene. On SSC2, a locus that significantly affects fatness traits mapped to the region around the IGF2 (insulin-like growth factor 2) gene but its non-imprinting inheritance excluded IGF2 as a candidate gene. A significant locus was also detected within a recombination cold spot that spans more than 30 Mb on SSCX, which hampered the identification of plausible candidate genes. Notably, no genome-wide significant locus was shared by the two experimental populations; different loci were observed that had both constant and time-specific effects on growth traits at different stages, which illustrates the complex genetic architecture of these traits.

Conclusions

We confirm several previously reported QTL and provide a list of novel loci for porcine growth and fatness traits in two experimental populations with Chinese Taihu and Western pigs as common founders. We showed that distinct loci exist for these traits in the two populations and identified HMGA1 and PLAG1 as strong candidate genes on SSC7 and SSC4, respectively.

Electronic supplementary material

The online version of this article (doi:10.1186/s12711-015-0089-5) contains supplementary material, which is available to authorized users.     

Genome-wide association study for longevity in the Holstein cattle population

Longevity is one of the most important traits determining dairy cow profitability. In the last decades dairy cows suffered a lowering in the age at culling. With the aim to identify the genes involved in longevity, dates of birth, yields, dates of calving during lifespan and culling dates were collected for 946 culled cows which had been genotyped with the Bovine High Density panel. Using the GenABEL package in R, genome-wide association analysis was performed on three potential traits of longevity: (1) ‘days in production,’ (2) ‘days in herd,’ (3) number of calvings over lifespan.’ Five genome-wide significant single nucleotide polymorphisms (SNPs) associated with all three longevity traits were detected. Several consecutive SNPs identified on chromosomes 16 and 30 indicated the presence of two suggestive quantitative trait loci (QTL). The genes comprised in the QTL regions had biological functions related to fertility, reproductive disorders, heat stress and welfare of cows. These findings might contribute to improving breeding strategies to improve longevity.     

Genome-wide association study on bipolar disorder in the Bulgarian population

Bipolar disorder is a severe psychiatric disorder influenced by environmental and genetic factors. Genetic studies have implicated many variants in the disease's etiology but only few have been successfully replicated. We conducted a genome-wide association study (GWAS) on bipolar disorder in the Bulgarian population followed by a replication study of the top 100 single nucleotide polymorphisms (SNPs) showing the smallest P values. The GWAS was performed on 188 bipolar disorder patients and 376 control subjects genotyped on the Illumina 550 platform. The replication study was conducted on 122 patients and 328 controls. Although our study did not show any association P value that achieved genome-wide significance, and none of the top 100 SNPs reached the Bonferroni-corrected P value in the replication study, the plausible involvement of some variants cannot be entirely discarded. Three polymorphisms, rs8099939 [P = 2.12 × 10(-6), odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.43-2.67] in GRIK5, rs6122972 (P = 3.11 × 10(-6), OR = 2.02, 95% CI = 1.46-2.80) in PARD6B and rs2289700 (P = 9.14 × 10(-6), OR = 2.13, 95% CI = 1.53-2.95) in CTSH remained associated at a similar level after Mantel-Haenszel test for combining the results from the genome-wide and replication studies. A modest association was also detected for SNP rs1012053 (GWAS P = 4.50 × 10(-2)) in DGKH, which has already been reported as the most significant variant in a previous genome-wide scan on bipolar disorder. However, further studies using larger datasets are needed to identify variants with smaller effects that contribute to the risk of bipolar disorder.     

Genome-wide two-locus epistasis scans in prostate cancer using two European populations

Approximately 40 single nucleotide polymorphisms (SNPs) that are associated with prostate cancer (PCa) risk have been identified through genome-wide association studies (GWAS). However, these GWAS-identified PCa risk-associated SNPs can explain only a small proportion of heritability (~13%) of PCa risk. Gene-gene interaction is speculated to be one of the major factors contributing to the so-called missing heritability. To evaluate the gene-gene interaction and PCa risk, we performed a two-stage genome-wide gene-gene interaction scan using a novel statistical approach named "Boolean Operation-based Screening and Testing". In the first stage, we exhaustively evaluated all pairs of SNP-SNP interactions for ~500,000 SNPs in 1,176 PCa cases and 1,101 control subjects from the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) study. No SNP-SNP interaction reached a genome-wide significant level of 4.4E-13. The second stage of the study involved evaluation of the top 1,325 pairs of SNP-SNP interactions (P(interaction) <1.0E-08) implicated in CGEMS in another GWAS population of 1,964 PCa cases from the Johns Hopkins Hospital (JHH) and 3,172 control subjects from the Illumina iControl database. Sixteen pairs of SNP-SNP interactions were significant in the JHH population at a P(interaction) cutoff of 0.01. However, none of the 16 pairs of SNP-SNP interactions were significant after adjusting for multiple tests. The current study represents one of the first attempts to explore the high-dimensional etiology of PCa on a genome-wide scale. Our results suggested a list of SNP-SNP interactions that can be followed in other replication studies.