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.

The Story of "I" Tracking: Psychological Implications of Self-Referential Language Use

We review extant research on the psychological implications of the use of first-person singular pronouns (i.e., “I-talk”). A common intuition is that I-talk is associated with an overly positive, highly agentic, and inflated view of the self—including arrogance, self-centeredness, and grandiose narcissism. Initial (small-sample) research provided evidence that frequent I-talk was associated with grandiose narcissism. More recent (large-sample) research, however, has found that the correlation is near zero. Frequent I-talk is, however, positively correlated with depressive symptoms, in particular, and negative emotionality (i.e., neuroticism), more broadly. Frequent I-talk is also positively related to the neurotic variety of narcissism called vulnerable narcissism. In addition, frequent I-talk has a positive association with sociodemographic characteristics such as (lower) status, (younger) age, and (female) gender; I-talk has a conditional association with truth-telling and authenticity—a correlation that appears to hinge on context. This review summarizes the literature on I-talk, provides some speculations about the emergent psychological meanings of I-talk, and provides a guide for future research.

Teacher Mindsets and Student Sense of Classroom Belonging

We investigate how teachers’ mindsets—or their beliefs about learning and school—relate to adolescents’ individual and collective reports of classroom belonging. Our pre-registered analyses of 1,200 middle school students show that teachers’ growth mindset and confidence in teaching positively relate to students’ math class belonging—explaining 40 percent of belonging among classes. Yet a teacher’s own sense of school belonging is unrelated to the belonging students feel in class. We also find that the conditional association between math teaching confidence and students’ classroom belonging is twice as strong for Black adolescents as it is for their White peers, and a teacher’s growth mindset has no bearing on Asian adolescents’ math class belonging.

Growth Matters: Disclosure and Risk Premium

Theoretical work generally predicts a negative association between disclosure and risk premium, where additional disclosure reduces estimation risk or information asymmetry. However, empirical studies frequently report mixed results. Recent theoretical studies suggest that the association between disclosure and risk premium is not necessarily always negative, and could be positive (or less negative). For example, Dutta and Nezlobin (2017) show that disclosure can be associated with higher risk premium when conditioned on firms' growth rates. Similarly, Johnstone (2016) shows that higher signal quality can lead to higher risk premium. Motivated by these studies, we re-examine the association between disclosure and risk premium, conditional on growth. Using various proxies for risk premium, disclosure, and growth, we provide robust evidence that while the unconditional association between disclosure and risk premium is ambiguous, the conditional association is negative for lower growth firms but is less negative (or positive) for higher growth firms.

Association of HLA-DQA2 and HLA-B With Moyamoya Disease in the Chinese Han Population

ObjectiveAn HLA imputation was conducted to explore the relationship between HLA and patients with moyamoya disease (MMD) in the Chinese Han population.MethodsIn this study, we performed an association analysis of the major histocompatibility complex region in 2,786 individuals of Chinese Han ancestry (2,031 controls and 755 patients with MMD), through a widely used HLA imputation method.ResultsWe identified that the variant rs3129731 (odds ratio [OR] = 1.79, p = 3.69 × 10−16) located between the MTCO3P1 and HLA-DQA2 is a major genetic risk factor for MMD. In addition to this variant, found in the conditional association analysis, we also detected another independent signal, rs1071817 (OR = 0.62, p = 1.20 × 10−11), in HLA-B.ConclusionsOur research suggests that the genetic polymorphism of HLA-DQA2 and HLA-B could be a genetic predisposing factor for MMD in Chinese Han. This may provide some evidence for further HLA-related studies of patients with MMD of Chinese Han ethnicity and indicates that MMD is an immune-related disease.

Primo: integration of multiple GWAS and omics QTL summary statistics for elucidation of molecular mechanisms of trait-associated SNPs and detection of pleiotropy in complex traits

To provide a comprehensive mechanistic interpretation of how known trait-associated SNPs affect complex traits, we propose a method, Primo, for integrative analysis of GWAS summary statistics with multiple sets of omics QTL summary statistics from different cellular conditions or studies. Primo examines association patterns of SNPs to complex and omics traits. In gene regions harboring known susceptibility loci, Primo performs conditional association analysis to account for linkage disequilibrium. Primo allows for unknown study heterogeneity and sample correlations. We show two applications using Primo to examine the molecular mechanisms of known susceptibility loci and to detect and interpret pleiotropic effects.

Genome-Wide Conditional Association Study Reveals the Influences of Lifestyle Cofactors on Genetic Regulation of Body Surface Area in MESA Population

Backgrounds Body surface area (BSA) is an important trait used for many clinical purposes and is associated with a variety of diseases including cardiovascular diseases and cancer. People's BSA may vary due to genetic background, race, and different lifestyle factors (such as walking, exercise, reading, smoking, transportation, etc.). Genome-wide association study of BSA was conducted on 5,336 subjects of four ethnic populations of European-American, African-American, Hispanic-American, and Chinese-American from MESA (The Multi-Ethnic Study of Atherocloris) data using unconditional and conditional full genetic models for analyzing genetic effects of additive, dominance, epistasis, and genetic by ethnicity interactions.Results Conditional association analyses revealed that lifestyle cofactors could affect the genetic effects of genes that regulate BSA. Moreover, impacts of the lifestyle cofactors on BSA could depend on the genotypes of several SNPs, and ethnicity of individuals. In this study, fifteen SNPs were identified with highly significant (Experiment-wise PEW < 1×10–5) genetic effects using unconditional full genetic model, of which thirteen SNPs had individual genetic effects and seven SNPs were involved in four pairs of epistasis interactions. Seven single SNPs and eight pairs of epistasis SNPs were additionally identified using exercise, smoking, and transportation cofactor-conditional models. Estimated heritabily was 72.88% using unconditional model and 74.85 ~ 79.87% using lifestyle cofactor-conditional models. It was revealed that lifestyle cofactors could contribute, suppress, increase or decrease the genetic effects of BSA associated genes. From gene ontology analysis, it was observed that several genes are related to the metabolic pathway of calcium compounds, a main compound in several diseases related to obesity, coronary artery disease, type-2 Diabetes, Alzheimer disease, childhood obesity, sleeping duration, Parkinson disease, and cancer.Conclusions In summary, our study provides novel insights into the genetic mechanism of BSA in MESA population, and influences of different lifestyle cofactors on the genetic effects of BSA associated loci.