What has GWAS done for HLA and disease associations?

The major histocompatibility complex (MHC) is located in chromosome 6p21 and contains crucial regulators of immune response, including human leucocyte antigen (HLA) genes, alongside other genes with nonimmunological roles. More recently, a repertoire of noncoding RNA genes, including expressed pseudogenes, has also been identified. The MHC is the most gene dense and most polymorphic part of the human genome. The region exhibits haplotype-specific linkage disequilibrium patterns, contains the strongest cis- and trans-eQTLs/meQTLs in the genome and is known as a hot spot for disease associations. Another layer of complexity is provided to the region by the extreme structural variation and copy number variations. While the HLA-B gene has the highest number of alleles, the HLA-DR/DQ subregion is structurally most variable and shows the highest number of disease associations. Reliance on a single reference sequence has complicated the design, execution and analysis of GWAS for the MHC region and not infrequently, the MHC region has even been excluded from the analysis of GWAS data. Here, we contrast features of the MHC region with the rest of the genome and highlight its complexities, including its functional polymorphisms beyond those determined by single nucleotide polymorphisms or single amino acid residues. One of the several issues with customary GWAS analysis is that it does not address this additional layer of polymorphisms unique to the MHC region. We highlight alternative approaches that may assist with the analysis of GWAS data from the MHC region and unravel associations with all functional polymorphisms beyond single SNPs. We suggest that despite already showing the highest number of disease associations, the true extent of the involvement of the MHC region in disease genetics may not have been uncovered.

Reactivity to unpredictable threat as a treatment target for fear-based anxiety disorders.

BACKGROUND: Heightened reactivity to unpredictable threat (U-threat) is a core individual difference factor underlying fear-based psychopathology. Little is known, however, about whether reactivity to U-threat is a stable marker of fear-based psychopathology or if it is malleable to treatment. The aim of the current study was to address this question by examining differences in reactivity to U-threat within patients before and after 12-weeks of selective serotonin reuptake inhibitors (SSRIs) or cognitive-behavioral therapy (CBT). METHODS: Participants included patients with principal fear (n = 22) and distress/misery disorders (n = 29), and a group of healthy controls (n = 21) assessed 12-weeks apart. A well-validated threat-of-shock task was used to probe reactivity to predictable (P-) and U-threat and startle eyeblink magnitude was recorded as an index of defensive responding. RESULTS: Across both assessments, individuals with fear-based disorders displayed greater startle magnitude to U-threat relative to healthy controls and distress/misery patients (who did not differ). From pre- to post-treatment, startle magnitude during U-threat decreased only within the fear patients who received CBT. Moreover, within fear patients, the magnitude of decline in startle to U-threat correlated with the magnitude of decline in fear symptoms. For the healthy controls, startle to U-threat across the two time points was highly reliable and stable. CONCLUSIONS: Together, these results indicate that startle to U-threat characterizes fear disorder patients and is malleable to treatment with CBT but not SSRIs within fear patients. Startle to U-threat may therefore reflect an objective, psychophysiological indicator of fear disorder status and CBT treatment response.

Investigations and implications of associations between mycobacterial purified protein derivative hypersensitivity and MAP-antibody ELISA in Irish dairy cows.

Intradermal testing, involving administration of purified protein derivative (PPD), to elicit a delayed hypersensitivity (DTH) response, is used as a diagnostic tool for bovine tuberculosis (bTB) and to aid in the identification of exposure to Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of Johne's disease (JD). Further research is required to increase the diagnostic value of skin testing for MAP. The aim of this study was to investigate if animals showing DTH reactions to PPD had an associated increase in MAP ELISA response, thereby identifying potential cases of sub-clinical JD. A 139-cow dairy herd was recruited to the study. During the mandatory annual bTB test, skin thickness measurements (mm) were recorded at the site of avian and bovine PPD administration. Cows were categorised based on recording no DTH, DTH at both PPD administration sites and DTH at one PPD site only. Blood samples were collected pre and post bTB testing, and ELISA tested. Generalised estimating equations were performed to identify associations between DTH responses and MAP ELISA results. Significant associations were identified between PPD DTH responses and MAP ELISA readings. Animals with DTH at both avian and bovine PPD sites were most likely to test ELISA positive in the post-PPD period relative to other categories. Further research is required to identify whether skin thickness increases post-PPD and associated increase in ELISA response, identifies animals previously exposed to MAP, or if results are due to cross reactivity.

Analysis of Johne's disease ELISA status and associated performance parameters in Irish dairy cows.

BACKGROUND: Infection with Mycobacterium avium subspecies paratuberculosis (MAP) has been associated with reductions in milk production in dairy cows and sub optimal fertility. The aim of this study was to highlight the production losses associated with testing MAP ELISA positive in Irish dairy cows. Secondary objectives included investigation of risk factors associated with testing MAP ELISA positive. A survey of management practices on study farms was also conducted, with examination of associations between management practices and herd MAP status. Blood samples were collected from 4188 breeding animals on 22 farms. Samples were ELISA tested using the ID Screen Paratuberculosis Indirect Screening Test. Production parameters examined included milk yield, milk fat, milk protein, somatic cell count, and calving interval. The association between MAP ELISA status and production data was investigated using multi-level mixed models. Logistic regression was used to identify risk factors for testing JD blood ELISA positive at individual cow level and to identify associations between farm management practices and herd MAP status. RESULTS: Data were available for 3528 cows. The apparent prevalence recorded was 7.4%. Mixed model analysis revealed no statistically significant association between testing MAP ELISA positive and dairy cow production parameters. Risk factors associated with testing positive included larger sized herds being over twice more likely to test positive than smaller herds (OR 2.4 P = <0.001). Friesians were less likely to test positive relative to other breeds. A number of study farmers were engaged in management practices that have previously been identified as high risk for MAP transmission e.g., 73.1% pooled colostrum and 84.6% of study farmers used the calving area to house sick animals throughout the year. No significant associations however, were identified between farm management practices and herd MAP status. CONCLUSION: No production losses were identified; however an apparent prevalence of 7.4% was recorded. With the abolition of EU milk quotas herd size in Ireland is expanding, as herds included in this study were larger than the national average, results may be indicative of future JD levels if no JD control programmes are implemented to minimise transmission.