SUMMARY The epigenome orchestrates genome accessibility, functionality and three-dimensional structure. Because epigenetic variation can impact transcription and thus phenotypes, it may contribute to adaptation. Here we report 1,107 high-quality single-base resolution methylomes and 1,203 transcriptomes from the 1001 Genomes collection of Arabidopsis thaliana. Although the genetic basis of methylation variation is highly complex, geographic origin is a major predictor of genome-wide DNA methylation levels and of altered gene expression caused by epialleles. Comparison to cistrome and epicistrome datasets identifies associations between transcription factor binding sites, methylation, nucleotide variation and co-expression modules. Physical maps for nine of the most diverse genomes reveals how transposons and other structural variants shape the epigenome, with dramatic effects on immunity genes. The 1001 Epigenomes Project provides a comprehensive resource for understanding how variation in DNA methylation contributes to molecular and non-molecular phenotypes in natural populations of the most studied model plant.

All human populations exhibit some level of genetic differentiation. This differentiation, or population stratification, has many interacting sources, including historical migrations, population isolation over time, genetic drift, and selection and adaptation. If differentiated populations remained isolated from each other over a long period of time such that there is no mating of individuals between those populations, then some level of global consanguinity within those populations will lead to the formation of gene pools that will become more and more distinct over time. Global genetic differentiation of this sort can lead to overt phenotypic differences between populations if phenotypically relevant variants either arise uniquely within those populations or begin to exhibit frequency differences across the populations. This can occur at the single variant level for monogenic phenotypes or at the level of aggregate variant frequency differences across the many loci that contribute to a phenotype with a multifactorial or polygenic basis. However, if individuals begin to interbreed (or ‘admix') from populations with different frequencies of phenotypically relevant genetic variants, then these admixed individuals will exhibit the phenotype to varying degrees. The level of phenotypic expression will depend on the degree to which the admixed individuals have inherited causative variants that have descended from the ancestral population in which those variants were present (or, more likely, simply more frequent). We review studies that consider the association between the degree of admixture (or ancestry) and phenotypes of clinical relevance. We find a great deal of literature-based evidence for associations between the degree of admixture and phenotypic variation for a number of admixed populations and phenotypes, although not all this evidence is confirmatory. We also consider the implications of such associations for gene-mapping initiatives as well as general clinical epidemiology studies and medical practice. We end with some thoughts on the future of studies exploring phenotypic differences among admixed individuals as well as individuals with different ancestral backgrounds.

Venetoclax and donor lymphocyte infusion for early relapsed acute myeloid leukemia after allogeneic hematopoietic cell transplantation. A retrospective multicenter trial. Ann Hematol. 2021;100(3): 817-824. 6. Zucenka A, Vaitekenaite V, Maneikis K, et al. Venetoclax-based salvage therapy followed by venetoclax and DLI maintenance vs. FLAG-Ida for relapsed or refractory acute myeloid leukemia after allogeneic stem cell transplantation.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland’s population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In a large Finnish biobank study FinnGen, we identified an association between an inframe insertion rs534125149 in MFGE8 (encoding lactadherin) and protection against coronary atherosclerosis. This variant is highly enriched in Finland, and the protective association was replicated in meta-analysis of BioBank Japan and Estonian biobank. Additionally, we identified a protective association between splice acceptor variant rs201988637 in MFGE8 and coronary atherosclerosis, independent of the rs534125149, with no significant risk-increasing associations. This variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial aging also in humans in addition to previous evidence in mice. In conclusion, our results suggest that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.