HLA-B27 and not variation in MICA is responsible for genotype by sex interaction in risk of Ankylosing Spondylitis

Ankylosing Spondylitis (AS) is a highly heritable inflammatory arthritis which occurs more frequently in men than women. In their recent publication examining sex differences in the genetic aetiology of common complex traits and diseases, Bernabeu et al. (2021) observe differences in heritability of AS between sexes, and a genome-wide significant genotype by sex interaction in risk of AS at the major histocompatability (MHC) locus. The authors then present evidence suggesting that this genotype by sex interaction arises primarily as a result of differential expression of the gene MICA across the sexes in skeletal muscle tissue. Through a series of conditional association analyses in the UK Biobank, reanalysis of the GTEx gene expression resource and RNASeq experiments on peripheral blood cells from AS cases and controls, we show that the genotype by sex interaction the authors' report is unlikely to be a result of variation in MICA, but probably reflects a known interaction between the HLA-B gene, sex and risk of AS. We demonstrate that the diagnostic accuracy of AS in the UK Biobank is low, particularly amongst women, likely explaining some of the observed differences in heritability across the sexes and the difficulty in precisely locating association signals in the cohort.

Diverse Functions Associate With Non-Coding Trans-species Polymorphisms in Humans

Background: Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species, hereafter “trans-species polymorphisms” (TSPs), often result from LTBS due to host-pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred candidate TSPs have been identified in humans and chimpanzees; however, because many are in non-coding regions of the genome, the functions and adaptive roles for most TSPs remain unknown. Results: We integrated diverse genomic annotations, with a focus on non-coding regions, to explore the functions of 125 previously identified regions containing multiple TSPs in humans and chimpanzees. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS). We identify functional annotations for 119 TSP regions, including 71 with evidence of gene regulatory function from GTEx or genome-wide functional genomics data and 21 with evidence of trait association from GWAS and PheWAS. TSPs in humans associate with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body mass, alcohol intake, urate levels, chronotype, and risk-taking behavior. Conclusions: The diversity of traits associated with non-coding human TSPs further support previous hypotheses that functions beyond the immune system are subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in great ape populations, such as the importance of variation in sleep cycles and risk sensitivity.

Cape Feather Coloration Signals Different Genotypes of the Most Polymorphic MHC Locus in Male Golden Pheasants (Chrysolophus pictus)

Ornamental feather coloration is usually a reflection of male quality and plays an important role during courtship, whereas the essence of male quality at the genetic level is not well understood. Major histocompatibility complex (MHC)-based mate choice has been observed in various vertebrates. Here, we investigated the relationship between the coloration of cape feathers and the MHC genotypes in golden pheasants (Chrysolophus pictus). We found that feather coloration differed sharply among different individuals (brightness: 1827.20 ± 759.43, chroma: 1241.90 ± 468.21, hue: 0.46 ± 0.06). Heterozygous individuals at the most polymorphic MHC locus (IA2) had brighter feathers than homozygous individuals (Z = −2.853, p = 0.004) and were more saturated in color (Z = −2.853, p = 0.004). However, feather coloration was not related to other MHC loci or to overall genetic heterozygosity (p > 0.050). Our study suggested that coloration of cape feathers might signal IA2 genotypes in golden pheasants.

Diverse functions associate with trans-species polymorphisms in humans

Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species, hereafter “trans-species polymorphisms” (TSPs), often result from LTBS due to host-pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred TSPs have been identified in humans and chimpanzees; however, because many are in non-coding regions of the genome, the functions and adaptive roles for most TSPs remain unknown. We integrated diverse genomic annotations to explore the functions of 125 previously identified non-coding TSPs that are likely under LTBS since the common ancestor of humans and chimpanzees. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS). We identify functional annotations for 119 TSP regions, including 71 with evidence of gene regulatory function from GTEx or genome-wide functional genomics data and 21 with evidence of trait association from GWAS and PheWAS. TSPs in humans associate with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body mass, alcohol intake, urate levels, chronotype, and risk-taking behavior. The diversity of traits associated with non-coding human TSPs suggest that functions beyond the immune system are often subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in great ape populations, such as the importance of variation in sleep cycles and risk sensitivity.Significance statementMost genetic variants present in human populations are young (<100,000 years old); however, a few hundred are millions of years old with origins before the divergence of humans and chimpanzees. These trans-species polymorphisms (TSPs) were likely maintained by balancing selection—evolutionary pressure to maintain genetic diversity at a locus. However, the functions driving this selection, especially for non-coding TSPs, are largely unknown. We integrate genome-wide annotation strategies to demonstrate TSP associations with immune system function, behavior (addition, cognition, risky behavior), uric acid metabolism, and many other phenotypes. These results substantially expand our understanding of functions TSPs and suggest a substantial role for balancing selection beyond the immune system.

Quantitative trait loci and transcriptome signatures associated with avian heritable resistance to Campylobacter

Campylobacter is the leading cause of bacterial foodborne gastroenteritis worldwide. Handling or consumption of contaminated poultry meat is a key risk factor for human campylobacteriosis. One potential control strategy is to select poultry with increased resistance to Campylobacter. We associated high-density genome-wide genotypes (600K single nucleotide polymorphisms) of 3000 commercial broilers with Campylobacter load in their caeca. Trait heritability was modest but significant (h2 = 0.11 ± 0.03). Results confirmed quantitative trait loci (QTL) on chromosomes 14 and 16 previously identified in inbred chicken lines, and detected two additional QTLs on chromosomes 19 and 26. RNA-Seq analysis of broilers at the extremes of colonisation phenotype identified differentially transcribed genes within the QTL on chromosome 16 and proximal to the major histocompatibility complex (MHC) locus. We identified strong cis-QTLs located within MHC suggesting the presence of cis-acting variation in MHC class I and II and BG genes. Pathway and network analyses implicated cooperative functional pathways and networks in colonisation, including those related to antigen presentation, innate and adaptive immune responses, calcium, and renin–angiotensin signalling. While co-selection for enhanced resistance and other breeding goals is feasible, the frequency of resistance-associated alleles was high in the population studied and non-genetic factors significantly influenced Campylobacter colonisation.

A global atlas of genetic associations of 220 deep phenotypes

The current genome-wide association studies (GWASs) do not yet capture sufficient diversity in terms of populations and scope of phenotypes. To address an essential need to expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype GWASs (disease endpoints, biomarkers, and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining results of electronic medical records. Meta-analyses with the harmonized phenotypes in the UK Biobank and FinnGen (ntotal = 628,000) identified over 4,000 novel loci, which substantially deepened the resolution of the genomic map of human traits, benefited from East Asian endemic diseases and East Asian specific variants. This atlas elucidated the globally shared landscape of pleiotropy as represented by the MHC locus, where we conducted fine-mapping by HLA imputation. Finally, to intensify the value of deep-phenotype GWASs, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified the latent genetic components, which pinpointed the responsible variants and shared biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (e.g., allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human disease classifications through genetics.

Integrative Genetics Analysis of Juvenile Idiopathic Arthritis Identifies Novel Loci

Juvenile Idiopathic Arthritis (JIA) is the most common type of arthritis among children, encompassing a highly heterogeneous group of immune-mediated joint disorders, being classified into seven subtypes based on clinical presentation. To systematically understand the distinct and shared genetic underpinnings of JIA subtypes, we conducted a heterogeneity-sensitive GWAS encompassing a total of 1245 JIA cases classified into 7 subtypes and 9250 controls. In addition to the MHC locus, we uncovered 16 genome-wide significant loci, among which 15 were shared between at least two JIA subtypes, including 11 novel loci. Functional annotation indicates that candidate genes at these loci are expressed in diverse immune cell types. Further, based on the association results, the 7 JIA subtypes were classified into two groups, reflecting their autoimmune vs autoinflammatory nature. Our results suggest a common genetic mechanism underlying these subtypes in spite of their different clinical disease phenotypes, and that there may be drug repositioning opportunities for rare JIA subtypes.