Epidemiologic studies recognize that trauma and posttraumatic stress are associated with heightened suicidal behavior severity, yet examination of these associations from a genetic perspective is limited. We performed a multivariate gene-by-environment genome-wide interaction study (GEWIS) of suicidality in 123,633 individuals using a covariance matrix based on 26 environments related to traumatic experiences, posttraumatic stress, social support, and socioeconomic status. We discovered five suicidality risk loci, including the male-associated rs2367967 (CWC22), which replicated in an independent cohort. All GEWIS-significant loci exhibited interaction effects where at least 5% of the sample had environmental profiles conferring opposite SNP effects from the majority. We identified PTSD as a primary driving environment for GxE at suicidality risk loci. The male suicidality GEWIS was enriched for three middle-temporal-gyrus inhibitory neuron transcriptomic profiles: SCUBE- and PVALB-expressing cells (β = 0.028, p = 3.74 × 10−4), OPRM1-expressing cells (β = 0.030, p = 0.001), and SPAG17-expressing cells (β = 0.029, p = 9.80 × 10−4). Combined with gene-based analyses (CNTN5 passociation = 2.38 × 10−9, pinteraction = 1.51 × 10−3; PSMD14 passociation = 2.04 × 10−7, pinteraction = 7.76 × 10−6; HEPACAM passociation = 2.43 × 10−6, pinteraction = 3.82 × 10−7) including information about brain chromatin interaction profiles (UBE2E3 in male neuron p = 1.07 × 10−5), our GEWIS points to extracellular matrix biology and synaptic plasticity as biological interactors with the effects of potentially modifiable lifetime traumatic experiences on genetic risk for suicidality. Characterization of molecular basis for the effects of traumatic experience and posttraumatic stress on risk of suicidal behaviors may help to identify novel targets for which more effective treatments can be developed for use in high-risk populations.

Background: Introgression from extinct Neanderthal and Denisovan human species has been shown to contribute to the genetic pool of modern human populations and their phenotypic spectrum. Evidence of how Neanderthal introgression shaped the genetics of human traits and diseases has been extensively studied in populations of European descent, with signatures of admixture reported for instance in genes associated with pigmentation, immunity, and metabolic traits. However, limited information is currently available about the impact of archaic introgression on other ancestry groups. Additionally, to date, no study has been conducted with respect to the impact of Denisovan introgression on the health and disease of modern populations. Here, we compare the way evolutionary pressures shaped the genetics of complex traits in East Asian and European populations, and provide evidence of the impact of Denisovan introgression on the health of East Asian and Central/South Asian populations.Results: Leveraging genome-wide association statistics from the Biobank Japan and UK Biobank, we assessed whether Denisovan and Neanderthal introgression together with other evolutionary genomic signatures were enriched for the heritability of physiological and pathological conditions in populations of East Asian and European descent. In EAS, Denisovan-introgressed loci were enriched for coronary artery disease heritability (1.69-fold enrichment,p=0.003). No enrichment for archaic introgression was observed in EUR. We also performed a phenome-wide association study of Denisovan and Neanderthal alleles in six ancestry groups available in the UK Biobank. In EAS, the Denisovan-introgressed SNP rs62391664 in the major histocompatibility complex region was associated with albumin/globulin ratio (beta=−0.17,p=3.57×10⁻⁷). Neanderthal-introgressed alleles were associated with psychiatric and cognitive traits in EAS (e.g., “No Bipolar or Depression”-rs79043717 beta=−1.5,p=1.1×10⁻⁷), and with blood biomarkers (e.g., alkaline phosphatase-rs11244089 beta=0.1,p=3.69×10⁻¹¹⁶) and red hair color (rs60733936 beta=−0.86,p=4.49×10⁻¹⁶⁵) in EUR. In the other ancestry groups, Neanderthal alleles were associated with several traits, also including the use of certain medications (e.g., Central/South East Asia: indapamide – rs732632 beta=−2.38,p=5.22×10⁻⁷).Conclusions: Our study provides novel evidence regarding the impact of archaic introgression on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in EAS populations.

This paper aims to provide a broad diet reconstruction for people buried in archaeologically defined contexts in Rome (first to third centuries CE), in order to combine archaeological and biological evidence focusing on dietary preferences in Imperial Rome. A sample of 214 human bones recovered from 6 funerary contexts was selected for carbon and nitrogen stable isotope analysis. The baseline for the terrestrial protein component of the diet was set using 17 coeval faunal remains recovered from excavations at Rome supplemented by previously published data for the same geographic and chronological frames. δ¹³C ranges from − 19.9 to − 14.8‰, whereas δ¹⁵N values are between 7.2 and 10.0‰. The values are consistent with an overall diet mainly based on terrestrial resources. All the human samples rely on a higher trophic level than the primary consumer faunal samples. Certainly, C₃plants played a pivotal role in the dietary habits. However, C₄plants also seem to have been consumed, albeit they were not as widespread and were not always used for human consumption. The environment played a critical role also for Romans of lower social classes. The topographical location determined the preferential consumption of food that people could obtain from their neighborhood.

Background: The Val122Ile mutation in Transthyretin ( TTR ) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other noncardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory/outpatient surgeries (OSs) in the country. Methods: We conducted first-ever epigenome-wide association study using the Illumina’s EPIC array, in Val122Ile carriers of African descent for heart disease and multiple OSs—an early disease indicator. Differential methylation across genome wide cytosine-phosphate guanine (CpG) sites was tested between carriers with and without heart disease and OS. Significant CpG sites were investigated for cis-mQTLs loci, followed by gene ontology and protein-protein interaction network. We also investigated the significant CpG sites in a secondary cohort of carriers for replication. Results: Five differentially methylated sites ( P ≤2.1×10 ⁻⁸ ) in genes— FAM129B , SKI , WDR27 , GLS , and an intergenic site near RP11-550A5.2, and one differentially methylated region containing KCNA6 and GALNT3 ( P =1.1×10 ⁻¹² ) were associated with heart disease. For OS, we observe 4 sites—2 sites in UBE2E3 and SEC14L5 , and other 2 in intergenic regions ( P ≤1.8×10 ⁻⁷ ) and 3 regions overlapping SH3D21 , EVA1B , LTB4R2 , and CIDEB ( P ≤3.9×10 ⁻⁷ ). Functional protein-interaction module analysis identified ABCA1 ( P =0.001) for heart disease. Six cis-mQTLs were associated with one of the significant CpG sites ( FAM129B ; P =4.1×10 ⁻²⁴ ). We replicated 2 CpG sites (cg18546846 and cg06641417; P <0.05) in an external cohort of biopsy-confirmed cases of TTR (transthyretin) amyloidosis. The genes identified are involved in transport and clearance of amyloid deposits ( GLS , ABCA1 , FAM129B ); cardiac fibrosis ( SKI ); and muscle tissue regulation ( SKI , FAM129B ). Conclusions: These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.

This paper aims to define the dietary profile of the population of early medieval Rome (fifth–eleventh centuries CE) by carbon and nitrogen stable isotope analysis. This period was characterized by deep changes in the city’s economic, demographic, and social patterns, probably affecting its inhabitants’ nutritional habits. Carbon and nitrogen stable isotope analysis of bone collagen was used to detect the nutritional profile of 110 humans from six communities inhabiting the city center of Rome and one from the ancient city of Gabii. Thirteen faunal remains were also analyzed to define the ecological baseline of the medieval communities. The isotopic results are consistent with a diet mainly based on the exploitation of C₃plant resources and terrestrial fauna, while the consumption of aquatic resources was detected only among the San Pancrazio population. Animal protein intake proved to be similar both among and within the communities, supporting a qualitatively homogenous dietary landscape in medieval Rome. The comparison with isotopic data from the Imperial Age allowed us to detect a diachronic nutritional transition in ancient Rome, in which the collapse of the Empire, and in particular the crisis of economic power and the trade system, represented a tipping point for its population’s nutritional habits.