Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis

A subset of patients with hypersensitivity pneumonitis (HP) develop lung fibrosis that is clinically similar to idiopathic pulmonary fibrosis (IPF). To address the aetiological determinants of fibrotic HP, we investigated whether the common IPF genetic risk variants were also relevant in study subjects with fibrotic HP. Our findings indicate that common genetic variants in TERC, DSP, MUC5B and IVD were significantly associated with fibrotic HP. These findings provide support for a shared etiology and pathogenesis between fibrotic HP and IPF.

COVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types

Common genetic polymorphisms associated with COVID-19 illness can be utilized for discovering molecular pathways and cell types driving disease pathogenesis. Given the importance of immune cells in the pathogenesis of COVID-19 illness, here we assessed the effects of COVID-19-risk variants on gene expression in a wide range of immune cell types. Transcriptome-wide association study and colocalization analysis revealed putative causal genes and the specific immune cell types where gene expression is most influenced by COVID-19-risk variants. Notable examples include OAS1 in non-classical monocytes, DTX1 in B cells, IL10RB in NK cells, CXCR6 in follicular helper T cells, CCR9 in regulatory T cells and ARL17A in TH2 cells. By analysis of transposase accessible chromatin and H3K27ac-based chromatin-interaction maps of immune cell types, we prioritized potentially functional COVID-19-risk variants. Our study highlights the potential of COVID-19 genetic risk variants to impact the function of diverse immune cell types and influence severe disease manifestations.

Genetic Link Determining the Maternal-Fetal Circulation of Vitamin D

Vitamin D is an essential micronutrient whose demand is heightened during pregnancy to support the growth of the fetus. Furthermore, the fetus does not produce vitamin D and hence relies exclusively on the supply of maternal vitamin D through the placenta. Vitamin D inadequacy is linked with pregnancy complications and adverse infant outcomes. Hence, early predictive markers of vitamin D inadequacy such as genetic vulnerability are important to both mother and offspring. In this multi-ethnic Asian birth cohort study, we report the first genome-wide association analysis (GWAS) of maternal and fetal vitamin D in circulation. For this, 25-hydroxyvitamin D (25OHD) was measured in the antenatal blood of mothers during mid gestation (n=942), and the cord blood of their offspring at birth (n=812). Around ~7 million single nucleotide polymorphisms (SNPs) were regressed against 25OHD concentrations to identify genetic risk variants. About 41% of mothers had inadequate 25OHD (≤75nmol/L) during pregnancy. Antenatal 25OHD was associated with ethnicity [Malay (Β=−22.32nmol/L, p=2.3×10−26); Indian (Β=−21.85, p=3.1×10−21); reference Chinese], age (Β=0.47/year, p=0.0058), and supplement intake (Β=16.47, p=2.4×10−13). Cord blood 25OHD highly correlated with antenatal vitamin D (r=0.75) and was associated with ethnicity [Malay (Β=−4.44, p=2.2×10−7); Indian (Β=−1.99, p=0.038); reference Chinese]. GWAS analysis identified rs4588, a missense variant in the group-specific component (GC) gene encoding vitamin D binding protein (VDBP), and its defining haplotype, as a risk factor for low antenatal (Β=−8.56/T-allele, p=1.0×10−9) and cord blood vitamin D (Β=−3.22/T-allele, p=1.0×10−8) in all three ethnicities. We also discovered a novel association in a SNP downstream of CYP2J2 (rs10789082), a gene involved in 25-hydroxylation of vitamin D, with vitamin D in pregnant women (Β=−7.68/G-allele, p=1.5×10−8), but not their offspring. As the prevention and early detection of suboptimal vitamin D levels are of profound importance to both mother and offspring’s health, the genetic risk variants identified in this study allow risk assessment and precision in early intervention of vitamin D deficiency.

DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses

Background: Depression is a disabling and highly prevalent condition where genetic and epigenetic differences, such as DNA methylation (DNAm), contribute to prediction of disease liability. Method: We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N=8,898, mean age=49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined=2,049, mean age=79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N=423, mean age=17.1 years). Result: Wide-spread associations were found between PRS constructed using genetic risk variants for depression and DNAm in cytosine- guanine dinucleotide (CpG) probes that localised to genes involved in immune responses and neural development (NCpG=599, pBonferroni<0.05, p<6.5e-8). The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r=0.83) and in adolescents (r=0.76). Additional analysis on the methylome-wide associations was conducted for each lead genetic risk variant. Over 40% of the independent genetic risk variants showed associations with CpG probe DNAm located in both the same (cis) and distal probes (trans) to the genetic loci (pBonferroni<0.045). Subsequent Mendelian randomisation analysis showed that DNAm and depression are mutually causal (pFDR<0.039), and there is a greater number of causal effects found from DNAm to depression (DNAm to depression: pFDR ranged from 0.045 to 2.06e-120; depression to DNAm: pFDR ranged from 0.046 to 2.1e-23). Conclusion: Polygenic risk scores for depression, especially those constructed from genome-wide significant genetic risk variants, showed epigenome-wide methylation association differences in the methylome associated with immune responses and brain development. We also found evidence from Mendelian randomisation evidence that DNAm may be causal to depression, as well as a causal consequence of depression.

Association of Common Genetic Risk Variants With Gestational Diabetes Mellitus and Their Role in GDM Prediction

ObjectiveWe aimed to explore the associations between common genetic risk variants with gestational diabetes mellitus (GDM) risk in Russian women and to assess their utility in the identification of GDM cases.MethodsWe conducted a case-control study including 1,142 pregnant women (688 GDM cases and 454 controls) enrolled at Almazov National Medical Research Centre. The International Association of Diabetes and Pregnancy Study Groups criteria were used to diagnose GDM. A total of 11 single- nucleotide polymorphisms (SNPs), including those in HKDC1 (rs10762264), GCK (rs1799884), MTNR1B (rs10830963 and rs1387153), TCF7L2 (rs7903146 and rs12255372), KCNJ11 (rs5219), IGF2BP2 (rs4402960), IRS1 (rs1801278), FTO (rs9939609), and CDKAL1 (rs7754840) were genotyped using Taqman assays. A logistic regression model was used to calculate odds ratios (ORs) and their confidence intervals (CIs). A simple-count genetic risk score (GRS) was calculated using 6 SNPs. The area under the receiver operating characteristic curve (c-statistic) was calculated for the logistic regression model predicting the risk of GDM using clinical covariates, SNPs that had shown a significant association with GDM in our study, GRS, and their combinations.ResultsTwo variants in MTNR1B (rs1387153 and rs10830963) demonstrated a significant association with an increased risk of GDM. The association remained significant after adjustment for age, pre-gestational BMI, arterial hypertension, GDM in history, impaired glucose tolerance, polycystic ovary syndrome, family history of diabetes, and parity (P = 0.001 and P &lt; 0.001, respectively). After being conditioned by each other, the effect of rs1387153 on GDM predisposition weakened while the effect of rs10830963 remained significant (P = 0.004). The risk of GDM was predicted by clinical variables (c-statistic 0.712, 95 % CI: 0.675 – 0.749), and the accuracy of prediction was modestly improved by adding GRS to the model (0.719, 95 % CI 0.682 – 0.755), and more by adding only rs10830963 (0.729, 95 % CI 0.693 – 0.764).ConclusionAmong 11 SNPs associated with T2D and/or GDM in other populations, we confirmed significant association with GDM for two variants in MTNR1B in Russian women. However, these variants showed limited value in the identification of GDM cases.