Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19

The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.

Identification of a Risk Locus at 7p22.3 for Schizophrenia and Bipolar Disorder in East Asian Populations

Background: Shared psychopathological features and mechanisms have been observed between schizophrenia (SZ) and bipolar disorder (BD), but their common risk genes and full genetic architectures remain to be fully characterized. The genome-wide association study (GWAS) datasets offer the opportunity to explore this scientific question using combined genetic data from enormous samples, ultimately allowing a better understanding of the onset and development of these illnesses.Methods: We have herein performed a genome-wide meta-analysis in two GWAS datasets of SZ and BD respectively (24,600 cases and 40,012 controls in total, discovery sample), followed by replication analyses in an independent sample of 4,918 SZ cases and 5,506 controls of Han Chinese origin (replication sample). The risk SNPs were then explored for their correlations with mRNA expression of nearby genes in multiple expression quantitative trait loci (eQTL) datasets.Results: The single nucleotide polymorphisms (SNPs) rs1637749 and rs3800908 at 7p22.3 region were significant in both discovery and replication samples, and exhibited genome-wide significant associations when combining all East Asian SZ and BD samples (29,518 cases and 45,518 controls). The risk SNPs were also significant in GWAS of SZ and BD among Europeans. Both risk SNPs significantly predicted lower expression of MRM2 in the whole blood and brain samples in multiple datasets, which was consistent with its reduced mRNA level in the brains of SZ patients compared with normal controls. The risk SNPs were also associated with MAD1L1 expression in the whole blood sample.Discussion: We have identified a novel genome-wide risk locus associated with SZ and BD in East Asians, adding further support for the putative common genetic risk of the two illnesses. Our study also highlights the necessity and importance of mining public datasets to explore risk genes for complex psychiatric diseases.

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness

More than 300 genetic risk loci have been identified for male pattern baldness (MPB) but little is known about the exact molecular mechanisms through which the associated variants exert their effects on MPB pathophysiology. Here, we aimed at further elucidating the regulatory architecture of the MPB risk locus on chromosome (chr.) 2q35, where we have previously reported a regulatory effect of the MPB lead variant on the expression of WNT10A. A HaploReg database research for regulatory annotations revealed that the association signal at 2q35 maps to a binding site for the transcription factor EBF1, whose gene is located at a second MPB risk locus on chr. 5q33.3. To investigate a potential interaction between EBF1 and WNT10A during MPB development, we performed in vitro luciferase reporter assays as well as expression analyses and immunofluorescence co-stainings in microdissected human hair follicles. Our experiments confirm that EBF1 activates the WNT10A promoter and that the WNT10A/EBF1 interaction is impacted by the allelic expression of the MPB risk allele at 2q35. Expression analyses across different hair cycle phases and immunhistochemical (co)stainings against WNT10A and EBF1 suggest a predominant relevance of EBF1/WNT10A interaction for hair shaft formation during anagen. Based on these findings we suggest a functional mechanism at the 2q35 risk locus for MPB, where an MPB-risk allele associated reduction in WNT10A promoter activation via EBF1 results in a decrease in WNT10A expression that eventually results in anagen shortening, that is frequently observed in MPB affected hair follicles. To our knowledge, this study is the first follow-up study on MPB that proves functional interaction between two MPB risk loci and sheds light on the underlying pathophysiological mechanism at these loci.

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we performed a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identified a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 x 10-8; KMT5B). We also identified a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N=1287) at 6p21.32 (rs3916765; P = 1.51 x 10 -10; HLA). Our results inform on AML etiology by identifying putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).