Major Histocompatibility Complex Loci Research Articles

Polygenic risk score-based phenome-wide association study of head and neck cancer across two large biobanks

BackgroundNumerous observational studies have highlighted associations of genetic predisposition of head and neck squamous cell carcinoma (HNSCC) with diverse risk factors, but these findings are constrained by design limitations of observational studies. In this study, we utilized a phenome-wide association study (PheWAS) approach, incorporating a polygenic risk score (PRS) derived from a wide array of genomic variants, to systematically investigate phenotypes associated with genetic predisposition to HNSCC. Furthermore, we validated our findings across heterogeneous cohorts, enhancing the robustness and generalizability of our results.MethodsWe derived PRSs for HNSCC and its subgroups, oropharyngeal cancer and oral cancer, using large-scale genome-wide association study summary statistics from the Genetic Associations and Mechanisms in Oncology Network. We conducted a comprehensive investigation, leveraging genotyping data and electronic health records from 308,492 individuals in the UK Biobank and 38,401 individuals in the Penn Medicine Biobank (PMBB), and subsequently performed PheWAS to elucidate the associations between PRS and a wide spectrum of phenotypes.ResultsWe revealed the HNSCC PRS showed significant association with phenotypes related to tobacco use disorder (OR, 1.06; 95% CI, 1.05–1.08; P = 3.50 × 10−15), alcoholism (OR, 1.06; 95% CI, 1.04–1.09; P = 6.14 × 10-9), alcohol-related disorders (OR, 1.08; 95% CI, 1.05–1.11; P = 1.09 × 10−8), emphysema (OR, 1.11; 95% CI, 1.06–1.16; P = 5.48 × 10−6), chronic airway obstruction (OR, 1.05; 95% CI, 1.03–1.07; P = 2.64 × 10−5), and cancer of bronchus (OR, 1.08; 95% CI, 1.04–1.13; P = 4.68 × 10−5). These findings were replicated in the PMBB cohort, and sensitivity analyses, including the exclusion of HNSCC cases and the major histocompatibility complex locus, confirmed the robustness of these associations. Additionally, we identified significant associations between HNSCC PRS and lifestyle factors related to smoking and alcohol consumption.ConclusionsThe study demonstrated the potential of PRS-based PheWAS in revealing associations between genetic risk factors for HNSCC and various phenotypic traits. The findings emphasized the importance of considering genetic susceptibility in understanding HNSCC and highlighted shared genetic bases between HNSCC and other health conditions and lifestyles.

Limited associations between MHC diversity and reproductive success in a bird species with biparental care.

The selective pressure from pathogens on individuals can have direct consequences on reproduction. Genes from the major histocompatibility complex (MHC) are central to the vertebrate adaptive immune system and pathogen resistance. In species with biparental care, each sex has distinct reproductive roles and levels of investment, and due to a trade-off with immunity, one can expect different selective regimes acting upon the MHC of each parent. Here, we addressed whether couples combine each other's variation at MHC loci to increase their breeding success. Specifically, we used a 23-year dataset from a barn owl population (Tyto alba) to understand how MHC class Iα and IIβ functional divergence and supertypes of each parent were associated with clutch size and fledging success. We did not detect associations between MHC diversity and supertypes with the clutch size or with the fledging success. In addition, to understand the relative contribution from the MHC of the genetic parents and the social parents, we analyzed the fledging success using only a cross-fostered dataset. We found several associations of weak-to-moderate effect sizes between the father's MHC and fledging success: (i) lower MHC-Iα divergence in the genetic father increases fledging success, which might improve paternal care during incubation, and (ii) one and two MHC-IIβ DAB2 supertypes in the social father decrease and increase, respectively, fledging success, which may affect the paternal care after hatching. Furthermore, fledging success increased when both parents did not carry MHC-IIβ DAB1 supertype 2, which could suggest conditional effects of this supertype. Although our study relied on a substantial dataset, we showed that the associations between MHC diversity and reproductive success remain scarce and of complex interpretation in the barn owl. Moreover, our results highlighted the need to incorporate more than one proxy of reproductive success and several MHC classes to capture more complex associations.

Gene-environment interaction in the pathophysiology of type 1 diabetes.

Type 1 diabetes (T1D) is a complex metabolic autoimmune disorder that affects millions of individuals worldwide and often leads to significant comorbidities. However, the precise trigger of autoimmunity and disease onset remain incompletely elucidated. This integrative perspective article synthesizes the cumulative role of gene-environment interaction in the pathophysiology of T1D. Genetics plays a significant role in T1D susceptibility, particularly at the major histocompatibility complex (MHC) locus and cathepsin H (CTSH) locus. In addition to genetics, environmental factors such as viral infections, pesticide exposure, and changes in the gut microbiome have been associated with the development of T1D. Alterations in the gut microbiome impact mucosal integrity and immune tolerance, increasing gut permeability through molecular mimicry and modulation of the gut immune system, thereby increasing the risk of T1D potentially through the induction of autoimmunity. HLA class II haplotypes with known effects on T1D incidence may directly correlate to changes in the gut microbiome, but precisely how the genes influence changes in the gut microbiome, and how these changes provoke T1D, requires further investigations. These gene-environment interactions are hypothesized to increase susceptibility to T1D through epigenetic changes such as DNA methylation and histone modification, which in turn modify gene expression. There is a need to determine the efficacy of new interventions that target these epigenetic modifications such as "epidrugs", which will provide novel avenues for the effective management of T1D leading to improved quality of life of affected individuals and their families/caregivers.

Evolutionary trade-offs constraining the MHC gene expansion: beyond simple TCR depletion model.

The immune system is as much shaped by the pressure of pathogens as it is by evolutionary trade-offs that constrain its structure and function. A perfect example comes from the major histocompatibility complex (MHC), molecules that initiate adaptive immune response by presentation of foreign antigens to T cells. The remarkable, population-level polymorphism of MHC genes is assumed to result mainly from a co-evolutionary arms race between hosts and pathogens, while the limited, within-individual number of functional MHC loci is thought to be the consequence of an evolutionary trade-off between enhanced pathogen recognition and excessive T cell depletion during negative selection in the thymus. Certain mathematical models and infection studies suggest that an intermediate individual MHC diversity would thus be optimal. A recent, more direct test of this hypothesis has shown that the effects of MHC diversity on T-cell receptor (TCR) repertoires may differ between MHC classes, supporting the depletion model only for MHC class I. Here, we used the bank vole (Myodes=Cletronomys glareolus), a rodent species with variable numbers of expressed MHC genes, to test how an individual MHC diversity influences the proportions and TCR repertoires of responding T cell subsets. We found a non-linear relationship between MHC diversity and T cell proportions (with intermediate MHC numbers coinciding with the largest T cell proportions), perhaps reflecting an optimality effect of balanced positive and negative thymic selection. The association was strongest for the relationship between MHC class I and splenic CD8+ T cells. The CD8+ TCR richness alone was unaffected by MHC class I diversity, suggesting that MHC class I expansion may be limited by decreasing T cell counts, rather than by direct depletion of TCR richness. In contrast, CD4+ TCR richness was positively correlated with MHC class II diversity, arguing against a universal TCR depletion. It also suggests that different evolutionary forces or trade-offs may limit the within-individual expansion of the MHC class II loci.

Association of HLA-A*11:01, -A*24:02, and -B*18:01 with Prostate Cancer Risk: A Case-Control Study.

The major histocompatibility complex (MHC) loci, the most polymorphic regions within the human genome, encode protein complexes responsible for antigen presentation and CD4+ and CD8+ cell activation. In prostate cancer (PCa), the second most diagnosed cancer in the male population, MHC loci undergo significant changes in their expression patterns, which affect the ability of the immune system to attack and eliminate malignant cells. The purpose of this study was to explore the genetic diversity of human leukocyte antigen (HLA)-A and HLA-B in patients with PCa and healthy controls (HCs) by performing HLA genotyping using NGS technology. The analysis highlighted statistically significant differences (p < 0.05) in the prevalence of three alleles (A*11:01, A*24:02, and B*18:01). Among the HCs analyzed, 14.89% had A*11:01, 20.21% had A*24:02, and 30.61% had B*18:01; while 5.21% of patients with PCa presented A*11:01, 9.38% presented A*24:02, 18.08% presented B*18:01. Odds ratio (OR) calculations underlined a negative association between the three alleles and the risk of PCa (OR < 1). The results presented in this study suggest a protective role of A*11:01, A*24:02, and B*18:01 in PCa.

De novo genome assembly depicts the immune genomic characteristics of cattle

Immunogenomic loci remain poorly understood because of their genetic complexity and size. Here, we report the de novo assembly of a cattle genome and provide a detailed annotation of the immunogenomic loci. The assembled genome contains 143 contigs (N50 ~ 74.0 Mb). In contrast to the current reference genome (ARS-UCD1.2), 156 gaps are closed and 467 scaffolds are located in our assembly. Importantly, the immunogenomic regions, including three immunoglobulin (IG) loci, four T-cell receptor (TR) loci, and the major histocompatibility complex (MHC) locus, are seamlessly assembled and precisely annotated. With the characterization of 258 IG genes and 657 TR genes distributed across seven genomic loci, we present a detailed depiction of immune gene diversity in cattle. Moreover, the MHC gene structures are integrally revealed with properly phased haplotypes. Together, our work describes a more complete cattle genome, and provides a comprehensive view of its complex immune-genome.

NOD mice have distinct metabolic and immunologic profiles when compared with genetically similar MHC-matched ICR mice.

Nonobese diabetic (NOD) mice are the most commonly used rodent model to study mechanisms relevant to the autoimmunity and immunology of type 1 diabetes. Although many different strains of mice have been used as controls for studies comparing nondiabetic lines to the NOD strain, we hypothesized that the parental strain that gave rise to the NOD line might be one of the best options. Therefore, we compared female ICR and NOD mice, which are matched at key major histocompatibility complex (MHC) loci, to understand their metabolic and immunologic similarities and differences. Several novel observations emerged: 1) NOD mice have greater circulating proinsulin when compared with ICR mice. 2) NOD mice display CD3+ and IBA1+ cell infiltration into and near pancreatic islets before hyperglycemia. 3) NOD mice show increased expression of the Il1b and Cxcl11 genes in islets when compared with islets from age-matched ICR mice. 4) NOD mice have a greater abundance of STAT1 and ICAM-1 protein in islets when compared with ICR mice. These data show that ICR mice, which are genetically similar to NOD mice, do not retain the same immunologic outcomes. Thus, ICR mice are an excellent choice as a genetically similar and MHC-matched control for NOD mice in studies designed to understand mechanisms relevant to autoimmune-mediated diabetes onset as well as novel therapeutic interventions.NEW & NOTEWORTHY Nonobese diabetic (NOD) mice have more proinsulin in circulation and STAT1 protein in islets compared with the major histocompatibility complex (MHC)-matched ICR line. NOD mice also display greater expression of cytokines and chemokines in pancreatic islets consistent with immune cell infiltration before hyperglycemia when compared with age-matched ICR mice. Thus, ICR mice represent an excellent control for autoimmunity and inflammation studies using the NOD line of mice.

Neutral Forces and Balancing Selection Interplay to Shape the Major Histocompatibility Complex Spatial Patterns in the Striped Hamster in Inner Mongolia: Suggestive of Broad-Scale Local Adaptation.

The major histocompatibility complex (MHC) plays a key role in the adaptive immune response to pathogens due to its extraordinary polymorphism. However, the spatial patterns of MHC variation in the striped hamster remain unclear, particularly regarding the relative contribution of the balancing selection in shaping MHC spatial variation and diversity compared to neutral forces. In this study, we investigated the immunogenic variation of the striped hamster in four wild populations in Inner Mongolia which experience a heterogeneous parasitic burden. Our goal was to identify local adaptation by comparing the genetic structure at the MHC with that at seven microsatellite loci, taking into account neutral processes. We observed significant variation in parasite pressure among sites, with parasite burden showing a correlation with temperature and precipitation. Molecular analysis revealed a similar co-structure between MHC and microsatellite loci. We observed lower genetic differentiation at MHC loci compared to microsatellite loci, and no correlation was found between the two. Overall, these results suggest a complex interplay between neutral evolutionary forces and balancing selection in shaping the spatial patterns of MHC variation. Local adaptation was not detected on a small scale but may be applicable on a larger scale.

Race/ethnicity-stratified fine-mapping of the MHC locus reveals genetic variants associated with late-onset asthma.

Introduction: Asthma is a chronic disease of the airways that impairs normal breathing. The etiology of asthma is complex and involves multiple factors, including the environment and genetics, especially the distinct genetic architecture associated with ancestry. Compared to early-onset asthma, little is known about genetic predisposition to late-onset asthma. We investigated the race/ethnicity-specific relationship among genetic variants within the major histocompatibility complex (MHC) region and late-onset asthma in a North Carolina-based multiracial cohort of adults. Methods: We stratified all analyses by self-reported race (i.e., White and Black) and adjusted all regression models for age, sex, and ancestry. We conducted association tests within the MHC region and performed fine-mapping analyses conditioned on the race/ethnicity-specific lead variant using whole-genome sequencing (WGS) data. We applied computational methods to infer human leukocyte antigen (HLA) alleles and residues at amino acid positions. We replicated findings in the UK Biobank. Results: The lead signals, rs9265901 on the 5' end of HLA-B, rs55888430 on HLA-DOB, and rs117953947 on HCG17, were significantly associated with late-onset asthma in all, White, and Black participants, respectively (OR = 1.73, 95%CI: 1.31 to 2.14, p = 3.62 × 10-5; OR = 3.05, 95%CI: 1.86 to 4.98, p = 8.85 × 10-6; OR = 19.5, 95%CI: 4.37 to 87.2, p = 9.97 × 10-5, respectively). For the HLA analysis, HLA-B*40:02 and HLA-DRB1*04:05, HLA-B*40:02, HLA-C*04:01, and HLA-DRB1*04:05, and HLA-DRB1*03:01 and HLA-DQB1 were significantly associated with late-onset asthma in all, White, and Black participants. Conclusion: Multiple genetic variants within the MHC region were significantly associated with late-onset asthma, and the associations were significantly different by race/ethnicity group.

Spatial Patterns of Neutral and Functional Genetic Variations along Dendritic Networks of Riverscape in Brown Trout Populations

Understanding how environmental gradients shape the spatial patterns of intraspecific genetic diversity is a central issue in ecological and evolutionary sciences. In riverine ecosystems, there is generally an increase in neutral genetic diversity downstream, as well as an increase in genetic differentiation among upstream populations. However, selective pressures may vary markedly along the upstream–downstream gradient, which could modify these patterns, but this has rarely been tested empirically. Here, we investigated how environmental gradients in a river network could shape the spatial patterns of intraspecific genetic diversity and differentiation in both neutral SNP markers and functional genetic markers putatively under natural selection (candidate SNPs associated with physiological functions and immune Major Histocompatibility Complex (MHC) loci) in wild brown trout populations. First, we showed that both the distance from the confluence and the centrality on the river network could explain the variation in genetic diversity and differentiation. Second, we found that both neutral and functional markers followed a similar pattern, with a higher genetic diversity and a lower genetic differentiation among populations that were more central and/or near to the confluence. This study highlights the importance of considering both the spatial and hydrological factors of a river network to understand and predict the role of dendritic connectivity in the spatial patterns of genetic diversity and differentiation in wild fish populations.

Genomes of two Extinct-in-the-Wild reptiles from Christmas Island reveal distinct evolutionary histories and conservation insights.

Genomics can play important roles in biodiversity conservation, especially for Extinct-in-the-Wild species where genetic factors greatly influence risk of total extinction and probability of successful reintroductions. The Christmas Island blue-tailed skink (Cryptoblepharus egeriae) and Lister's gecko (Lepidodactylus listeri) are two endemic reptile species that went extinct in the wild shortly after the introduction of a predatory snake. After a decade of management, captive populations have expanded from 66 skinks and 43 geckos to several thousand individuals; however, little is known about patterns of genetic variation in these species. Here, we use PacBio HiFi long-read and Hi-C sequencing to generate highly contiguous reference genomes for both reptiles, including the XY chromosome pair in the skink. We then analyse patterns of genetic diversity to infer ancient demography and more recent histories of inbreeding. We observe high genome-wide heterozygosity in the skink (0.007 heterozygous sites per base-pair) and gecko (0.005), consistent with large historical population sizes. However, nearly 10% of the blue-tailed skink reference genome falls within long (>1Mb) runs of homozygosity (ROH), resulting in homozygosity at all major histocompatibility complex (MHC) loci. In contrast, we detect a single ROH in Lister's gecko. We infer from the ROH lengths that related skinks may have established the captive populations. Despite a shared recent extinction in the wild, our results suggest important differences in these species' histories and implications for management. We show how reference genomes can contribute evolutionary and conservation insights, and we provide resources for future population-level and comparative genomic studies in reptiles.

Risk HLA Variants Affect the T-Cell Repertoire in Multiple Sclerosis.

The major histocompatibility complex (MHC) locus has a predominant role in the genetic predisposition to multiple sclerosis (MS), with 32 associations found to be involved. We aimed to investigate the impact of MHC MS-risk alleles on T-cell repertoire in patients with MS. We studied 161 untreated patients with relapsing-remitting MS for whom Class I and II human leukocyte antigen (HLA) alleles were inferred from whole-genome genotyping data, and T-cell receptor (TCR) CDR3 sequences were obtained through next-generation sequencing. T-cell repertoire features including diversity, public clones, and architecture were evaluated. We identified 5 MS-risk loci associated with TCR diversity: HLA-DRB1*15:01 (7.65 × 10-3), rs9271366 (1.96 × 10-3), rs766848979 A (1.89 × 10-2), rs9277626 (2.95 × 10-2), and rs11751659 (1.92 × 10-2), with evidence of expanded clonotypes in carriers of risk alleles. Moreover, HLA-DRB1*15:01 (4.99 × 10-3), rs9271366 (6.54 × 10-3), rs1049079 C (4.37 × 10-2), AA DQΒ1 position -5 L (1.05 × 10-3), and AA DQΒ1 position 221 Q (9.39 × 10-4) showed an association with the CDR3 aminoacidic sequence architecture, suggesting an impact on the antigen recognition breadth as well. Evaluating the sharing of clones across MS-risk allele carrier individuals revealed the presence of highly shared clonotypes predicted to target viral antigens, including Epstein-Barr virus. Our study supports the association between MHC-risk alleles and macrofeatures of the T-cell repertoire in the context of MS. Further studies are needed to understand the underlying molecular mechanisms.

Cross-Trait Mendelian Randomization Study to Investigate Whether Migraine Is a Risk Factor for Multiple Sclerosis.

Migraine is common among people with multiple sclerosis (MS), but the reasons for this are unknown. We tested 3 hypothesized mechanisms for this observed comorbidity, including migraine is a risk factor of MS, genetic variants are shared between the conditions, and migraine is because of MS. Data were from 2 sources: publicly available summary statistics from genome-wide association studies of MS (N = 115,748) and migraine (N = 375,752 and N = 361,141) and a case-control study of MS recruited from the Kaiser Permanente Northern California Health Plan (N = 1,991). For the latter participants, migraine status was ascertained using a validated electronic health record migraine probability algorithm or self-report. Using the public summary statistics, we used 2-sample Mendelian randomization to test whether a migraine genetic instrumental variable was associated with MS. We used linkage disequilibrium score regression and LOGODetect to ascertain whether MS and migraine shared genetic variants across the genome and regionally. Using the Northern California MS cohort, we used logistic regression to identify whether people with both MS and migraine had different odds of clinical characteristics (e.g., age at MS onset, Perceived Deficits Questionnaire, and depression) or MS-specific risk factors (e.g., body mass index, smoking status, and infectious mononucleosis status) compared with people with MS without migraine. We did not find evidence supporting migraine as a causal risk factor of MS (p = 0.29). We did, however, identify 4 major histocompatibility complex (MHC) loci shared between MS and migraine. Among the Northern California MS cohort, 774 (39%) experienced migraine. People with both MS and migraine from this cohort were more likely to ever smoke (odds ratio [OR] = 1.30, 95% CI: 1.08-1.57), have worse self-reported cognitive deficits (OR = 1.04, 95% CI: 1.02-1.06), and ever experience depression (OR = 1.48, 95% CI: 1.22-1.80). Our findings do not support migraine as a causal risk factor of MS. Several genetic variants, particularly in the MHC, may account for some of the overlap. It seems likely that migraine within the context of MS is because of MS. Identifying what increases the risk of migraine within MS might lead to an improved treatment and quality of life.

Diversifying selection and climatic effects on major histocompatibility complex class II gene diversity in the greater horseshoe bat.

Heterogeneous pathogenic stress can shape major histocompatibility complex (MHC) diversity by influencing the functional plasticity of the immune response. Therefore, MHC diversity could reflect environmental stress, demonstrating its importance in uncovering the mechanisms of adaptive genetic variation. In this study, we combined neutral microsatellite loci, an immune-related MHC II-DRB locus, and climatic factors to unravel the mechanisms affecting the diversity and genetic differentiation of MHC genes in the greater horseshoe bat (Rhinolophus ferrumequinum), a species with a wide geographical distribution that has three distinct genetic lineages in China. First, increased genetic differentiation at the MHC locus among populations compared using microsatellites indicated diversifying selection. Second, the genetic differentiation of MHC and microsatellites were significantly correlated, suggesting that demographic processes exist. However, MHC genetic differentiation was significantly correlated with geographical distance among populations, even after controlling for the neutral markers, suggesting a major effect of selection. Third, although the MHC genetic differentiation was larger than that for microsatellites, there was no significant difference in the genetic differentiation between the two markers among genetic lineages, indicating the effect of balancing selection. Fourth, combined with climatic factors, MHC diversity and supertypes showed significant correlations with temperature and precipitation, but not with the phylogeographic structure of R. ferrumequinum, suggesting an effect of local adaptation driven by climate on MHC diversity. Moreover, the number of MHC supertypes varied between populations and lineages, suggesting regional characteristics and support for local adaptation. Taken together, the results of our study provide insights into the adaptive evolutionary driving forces at different geographic scales in R. ferrumequinum. In addition, climate factors may have played a vital role in driving adaptive evolution in this species.

Exploring the Genetic Link Between Thyroid Dysfunction and Common Psychiatric Disorders: A Specific Hormonal or a General Autoimmune Comorbidity.

Background: The hypothalamus-pituitary-thyroid axis coordinates brain development and postdevelopmental function. Thyroid hormone (TH) variations, even within the normal range, have been associated with the risk of developing common psychiatric disorders, although the underlying mechanisms remain poorly understood. Methods: To get new insight into the potentially shared mechanisms underlying thyroid dysfunction and psychiatric disorders, we performed a comprehensive analysis of multiple phenotypic and genotypic databases. We investigated the relationship of thyroid disorders with depression, bipolar disorder (BIP), and anxiety disorders (ANXs) in 497,726 subjects from U.K. Biobank. We subsequently investigated genetic correlations between thyroid disorders, thyrotropin (TSH), and free thyroxine (fT4) levels, with the genome-wide factors that predispose to psychiatric disorders. Finally, the observed global genetic correlations were furthermore pinpointed to specific local genomic regions. Results: Hypothyroidism was positively associated with an increased risk of major depressive disorder (MDD; OR = 1.31, p = 5.29 × 10-89), BIP (OR = 1.55, p = 0.0038), and ANX (OR = 1.16, p = 6.22 × 10-8). Hyperthyroidism was associated with MDD (OR = 1.11, p = 0.0034) and ANX (OR = 1.34, p = 5.99 × 10-⁶). Genetically, strong coheritability was observed between thyroid disease and both major depressive (rg = 0.17, p = 2.7 × 10-⁴) and ANXs (rg = 0.17, p = 6.7 × 10-⁶). This genetic correlation was particularly strong at the major histocompatibility complex locus on chromosome 6 (p < 10-⁵), but further analysis showed that other parts of the genome also contributed to this global effect. Importantly, neither TSH nor fT4 levels were genetically correlated with mood disorders. Conclusions: Our findings highlight an underlying association between autoimmune hypothyroidism and mood disorders, which is not mediated through THs and in which autoimmunity plays a prominent role. While these findings could shed new light on the potential ineffectiveness of treating (minor) variations in thyroid function in psychiatric disorders, further research is needed to identify the exact underlying molecular mechanisms.

Association of Human Leukocyte Antigen Variants with Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Background: Multiple Myeloma (MM), a neoplasm of terminally differentiated plasma cells that produce a monoclonal immunoglobulin, represents 10% of hematologic malignancies. Virtually all MM arises from monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant phase, at a rate of progression of about 1% annually. However, the risk of progression is not uniform as some individuals with MGUS could have progression rates as high as 58% in 20 years. Novel predictive markers are critically needed to accurately identify MGUS patients at high-risk of malignant transformation, so that early intervention can be implemented to prevent end-organ damage associated with frank myeloma. Genome-wide association studies (GWAS) have repeatedly identified loci at the major histocompatibility complex (MHC) that are associated with the risk of many cancers including MM. However, the impact of specific MHC loci on the MGUS-to-MM progression risk has not been elucidated. Methods: We used the Illumina Infinium Global Screening Array to scan the buffy coat samples of 259 MGUS and 654 MM patients enrolled from the Medical College of Wisconsin (MCW) Tissue Bank. All MGUS and MM patients have been chart reviewed and confirmed diagnosis. After a standard quality control (QC), 249 MGUS and 619 MM patients with 11,882 genotyped single nucleotide polymorphisms (SNPs) in the MHC region (20 to 40 mb at chromosome 6) were used for analysis. The SNP2HLA v1.0.3 software and HLA*IMP:03 were applied to impute classical human leukocyte antigen (HLA) alleles at a four-digit resolution based on SNP genotyping. SNP2HLA uses Beagle to impute all missing SNPs, classical HLA alleles, and amino acid polymorphisms to the HapMap reference panel. HLA*IMP:03 uses the Michigan Imputation Server to impute phased haplotypes to a multi-ethnic panel of 10,561 individuals with SNP genotype data and lab-based typing of alleles at 11 HLA genes. A post-imputation QC was conducted to remove variants with low imputation quality score (R2 < 0.3). Logistic regression analysis was performed using PLINK, a whole genome association analysis toolset, which adjusted for age, race, sex, and top principal components. Results: As evidenced by the quantile-quantile (QQ) plot (Figure 1), there was no evidence for hidden substructure or cryptic relatedness in the GWAS (λ=1.02). The final set of imputed variants from both tools used in association analysis were of high quality (R2 ≥0.9). Although we did not observe any HLA variants showing associations with the progression of MGUS to MM at Bonferroni adjusted significance level for SNP2HLA (P = 0.05/5865 = 8.53 × 10-6) and for HLA*IMP:03 (P = 0.05/215 = 2.33 × 10-4), we found 4 classical HLA alleles and 30 HLA Amino Acids were associated with MGUS progression at a P-value of < 0.05 via association analysis with SNP2HLA. Association analysis for HLA*IMP:03 imputation data identified 8 classical HLA alleles were associated with MGUS progression at P value < 0.05. Among them, two classical HLA alleles were identified in both tools, they are HLA_B*08:01 (odds ratio, OR=0.38, 95% confidence interval, CI =0.19-0.77 and OR=0.43, 95% CI=0.21-0.86 for SNP2HLA and HLA*IMP:03, respectively) and HLA_C*07:01 (OR=0.61, 95% CI=0.41-0.89 and OR=0.63, 95% CI=0.41-0.98 for SNP2HLA and HLA*IMP:03, respectively) (Table 1). Conclusions: These results implicate that HLA alleles may contribute to the progression of MGUS to MM. Further studies are needed to validate our findings with larger sample sizes and explore the biological mechanisms. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.

Relationship between genome-wide and MHC class I and II genetic diversity and complementarity in a nonhuman primate.

Although mate choice is expected to favor partners with advantageous genetic properties, the relative importance of genome‐wide characteristics, such as overall heterozygosity or kinship, versus specific loci, is unknown. To disentangle genome‐wide and locus‐specific targets of mate choice, we must first understand congruence in global and local variation within the same individual. This study compares genetic diversity, both absolute and relative to other individuals (i.e., complementarity), assessed across the genome to that found at the major histocompatibility complex (MHC), a hyper‐variable gene family integral to immune system function and implicated in mate choice across species. Using DNA from 22 captive olive baboons (Papio anubis), we conducted double digest restriction site‐associated DNA sequencing to estimate genome‐wide heterozygosity and kinship, and sequenced two class I and two class II MHC loci. We found that genome‐wide diversity was not associated with MHC diversity, and that diversity at class I MHC loci was not correlated with diversity at class II loci. Additionally, kinship was a significant predictor of the number of MHC alleles shared between dyads at class II loci. Our results provide further evidence of the strong selective pressures maintaining genetic diversity at the MHC in comparison to other randomly selected sites throughout the genome. Furthermore, our results indicate that class II MHC disassortative mate choice may mediate inbreeding avoidance in this population. Our study suggests that mate choice favoring genome‐wide genetic diversity is not always synonymous with mate choice favoring MHC diversity, and highlights the importance of controlling for kinship when investigating MHC‐associated mate choice.

Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene

SummaryThe host genetic factors conferring protection against HIV type 1 (HIV-1) acquisition remain elusive, and in particular the contributions of common genetic variants. Here, we performed the largest genome-wide association meta-analysis of HIV-1 acquisition, which included 7,303 HIV-1-positive individuals and 587,343 population controls. We identified 25 independent genetic loci with suggestive association, of which one was genome-wide significant within the major histocompatibility complex (MHC) locus. After exclusion of the MHC signal, linkage disequilibrium score regression analyses revealed a SNP heritability of 21% and genetic correlations with behavioral factors. A transcriptome-wide association study identified 15 susceptibility genes, including HERC1, UEVLD, and HIST1H4K. Convergent evidence from conditional analyses and fine-mapping identified HERC1 downregulation in immune cells as a robust mechanism associated with HIV-1 acquisition. Functional studies on HERC1 and other identified candidates, as well as larger genetic studies, have the potential to further our understanding of the host mechanisms associated with protection against HIV-1.

Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis.

ObjectiveJuvenile idiopathic arthritis (JIA) is the most common chronic immune‐mediated joint disease among children and encompasses a heterogeneous group of immune‐mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes.MethodsWe performed a heterogeneity‐sensitive genome‐wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine‐mapping of candidate causal variants at each genome‐wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses.ResultsIn addition to the major histocompatibility complex locus, we identified 15 genome‐wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types.ConclusionThis study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.