Interaction of Alu Polymorphisms and Novel Measures of Discrimination in Association with Blood Pressure in African Americans Living in Tallahassee

African Americans are 40% more likely to be afflicted with hypertension in comparison to non-Hispanic, white Americans, resulting in a 30% higher instance of mortality due to cardiovascular disease. There is debate about the relative contributions of genetic and sociocultural risk factors to the racial disparity in hypertension. We assayed three Alu insertion polymorphisms located in the angiotensin-1-converting enzyme (ACE), tissue plasminogen activator (PLAT), and with no-lysine kinase 1 (WNK1) genes. We also estimated West African genetic ancestry and developed novel measures of perceived discrimination to create a biocultural model of blood pressure among African- American adults in Tallahassee, FL (n=158). When tested separately, the ACE Alu non-insertion allele was significantly associated with higher systolic and diastolic blood pressure. In multiple regression analyses, West African genetic ancestry was not associated with blood pressure and reduced the strength of all blood pressure models tested. A gene x environment interaction was identified between the ACE Alu genotype and a new measure of unfair treatment that includes experiences by individuals close to the study participant. Inclusion of the WNK1 Alu genotype further improved this model of blood pressure variation. Our results suggest an association of the ACE and WNK1 genotypes with blood pressure that is consistent with their proposed gene functions. Perceived unfair treatment (to others) shows a threshold effect where an increase in blood pressure is demonstrated at higher values. The interaction between the ACE genotype and unfair treatment highlights the benefits of including both genetic and cultural data to investigate complex disease

<i>BNDF </i>methylation in mothers and newborns is associated with maternal exposure to war trauma

Abstract Background The BDNF gene codes for brain-derived neurotrophic factor, a growth factor involved in neural development, cell differentiation, and synaptic plasticity. Present in both the brain and periphery, BDNF plays critical roles throughout the body and is essential for placental and fetal development. Rodent studies show that early life stress, including prenatal stress, broadly alters BDNF methylation, with presumed changes in gene expression. No studies have assessed prenatal exposure to maternal traumatic stress and BDNF methylation in humans. This study examined associations of prenatal exposure to maternal stress and BDNF methylation at CpG sites across the BDNF gene. Results Among 24 mothers and newborns in the eastern Democratic Republic of Congo, a region with extreme conflict and violence to women, maternal experiences of war trauma and chronic stress were associated with BDNF methylation in umbilical cord blood, placental tissue, and maternal venous blood. Associations of maternal stress and BDNF methylation showed high tissue specificity. The majority of significant associations were observed in putative transcription factor binding regions. Conclusions This is the first study in humans to examine BDNF methylation in relation to prenatal exposure to maternal stress in three tissues simultaneously and the first in any mammalian species to report associations of prenatal stress and BDNF methylation in placental tissue. The findings add to the growing body of evidence highlighting the importance of considering epigenetic effects when examining the impacts of trauma and stress, not only for adults but also for offspring exposed via effects transmitted before birth

Updated Three-Stage Model for the Peopling of the Americas

Background: We re-assess support for our three stage model for the peopling of the Americas in light of a recent report that identified nine non-Native American mitochondrial genome sequences that should not have been included in our initial analysis. Removal of these sequences results in the elimination of an early (i.e.,40,000 years ago) expansion signal we had proposed for the proto-Amerind population. Methodology/Findings: Bayesian skyline plot analysis of a new dataset of Native American mitochondrial coding genomes confirms the absence of an early expansion signal for the proto-Amerind population and allows us to reduce the variation around our estimate of the New World founder population size. In addition, genetic variants that define New World founder haplogroups are used to estimate the amount of time required between divergence of proto-Amerinds from the Asian gene pool and expansion into the New World. Conclusions/Significance: The period of population isolation required for the generation of New World mitochondrial founder haplogroup-defining genetic variants makes the existence of three stages of colonization a logical conclusion. Thus, our three stage model remains an important and useful working hypothesis for researchers interested in the peopling of th

Allelic variation at alcohol metabolism genes ( ADH1B , ADH1C , ALDH2 ) and alcohol dependence in an American Indian population

Enzymes encoded by two gene families, alcohol dehydrogenase ( ADH ) and aldehyde dehydrogenase ( ALDH ), mediate alcohol metabolism in humans. Allelic variants have been identified that alter metabolic rates and influence risk for alcoholism. Specifically, ADH1B*47His (previously ADH2-2 ) and ALDH2-2 have been shown to confer protection against alcoholism, presumably through accumulation of acetaldehyde in the blood and a resultant 'flushing response' to alcohol consumption. In the current study, variants at ADH1B (previously ADH2 ), ADH1C (previously ADH3 ), and ALDH2 were assayed in DNA extracts from participants belonging to a Southwest American Indian tribe ( n =490) with a high prevalence of alcoholism. Each subject underwent a clinical interview for diagnosis of alcohol dependence, as well as evaluation of intermediate phenotypes such as binge drinking and flushing response to alcohol consumption. Detailed haplotypes were constructed and tested against alcohol dependence and related intermediate phenotypes using both association and linkage analysis. ADH and ALDH variants were also assayed in three Asian and one African population (no clinical data) in order to provide an evolutionary context for the haplotype data. Both linkage and association analysis identified several ADH1C alleles and a neighboring microsatellite marker that affected risk of alcohol dependence and were also related to binge drinking. These data strengthen the support for ADH as a candidate locus for alcohol dependence and suggest further productive study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47592/1/439_2003_Article_971.pd

A Three-Stage Colonization Model for the Peopling of the Americas

Background: We evaluate the process by which the Americas were originally colonized and propose a three-stage model that integrates current genetic, archaeological, geological, and paleoecological data. Specifically, we analyze mitochondrial and nuclear genetic data by using complementary coalescent models of demographic history and incorporating nongenetic data to enhance the anthropological relevance of the analysis. Methodology/Findings: Bayesian skyline plots, which provide dynamic representations of population size changes over time, indicate that Amerinds went through two stages of growth &lt;40,000 and &lt;15,000 years ago separated by a long period of population stability. Isolation-with-migration coalescent analyses, which utilize data from sister populations to estimate a divergence date and founder population sizes, suggest an Amerind population expansion starting &lt;15,000 years ago. Conclusions/Significance: These results support a model for the peopling of the New World in which Amerind ancestors diverged from the Asian gene pool prior to 40,000 years ago and experienced a gradual population expansion as they moved into Beringia. After a long period of little change in population size in greater Beringia, Amerinds rapidly expanded into the Americas &lt;15,000 years ago either through an interior ice-free corridor or along the coast. This rapid colonization of the New World was achieved by a founder group with an effective population size of &lt;1,000–5,400 individuals. Our model presents a detailed scenario for the timing and scale of the initial migration to the Americas, substantially refines th

Beringian Standstill and Spread of Native American Founders

Native Americans derive from a small number of Asian founders who likely arrived to the Americas via Beringia. However, additional details about the intial colonization of the Americas remain unclear. To investigate the pioneering phase in the Americas we analyzed a total of 623 complete mtDNAs from the Americas and Asia, including 20 new complete mtDNAs from the Americas and seven from Asia. This sequence data was used to direct high-resolution genotyping from 20 American and 26 Asian populations. Here we describe more genetic diversity within the founder population than was previously reported. The newly resolved phylogenetic structure suggests that ancestors of Native Americans paused when they reached Beringia, during which time New World founder lineages differentiated from their Asian sister-clades. This pause in movement was followed by a swift migration southward that distributed the founder types all the way to South America. The data also suggest more recent bi-directional gene flow between Siberia and the North American Arctic

Data from: Testing support for the northern and southern dispersal routes out of Africa: an analysis of Levantine and southern Arabian populations

Objectives: The Northern Dispersal Route (NDR) and Southern Dispersal Route (SDR) are hypothesized to have been used by modern humans in the dispersal out of Africa. The NDR follows the Nile into Northeast Africa and crosses the Red Sea into the Levant. The SDR emerges from the Horn of Africa and crosses the Bab el-Mandeb into southern Arabia. In this study, we analyze genetic data from populations living along the NDR and SDR to test support for each dispersal route. Materials and methods: We genotyped 90 Yemeni samples on the Affymetrix Human Origins array. We analyzed these data with published data from Levantine and other southern Arabian populations as well as 157 comparative populations for a total sample size of >550,000 genetic variants from >2,000 individuals in >160 populations. We calculated outgroup f3 statistics to test how Levantine and southern Arabian populations relate to African populations living along the NDR and SDR and to other non-African populations. Results: We find that Levantine and southern Arabian populations bear similar genetic relationships to both African and non-African populations, thus providing no support for the use of one dispersal route over the other. Discussion: Our results are consistent with a history of gene flow between the Levant and southern Arabia. Consideration of genetic, archaeological, and paleoclimate data provide a slight edge for the SDR but, ultimately, more data are needed to definitively identify which dispersal route out of Africa was used

Prenatal maternal stress is associated with site-specific and age acceleration changes in maternal and newborn DNA methylation

Prenatal maternal stress has a negative impact on child health but the mechanisms through which maternal stress affects child health are unclear. Epigenetic variation, such as DNA methylation, is a likely mechanistic candidate as DNA methylation is sensitive to environmental insults and can regulate long-term changes in gene expression. We recruited 155 mother-newborn dyads in the Democratic Republic of Congo to investigate the effects of maternal stress on DNA methylation in mothers and newborns. We used four measures of maternal stress to capture a range of stressful experiences: general trauma, sexual trauma, war trauma, and chronic stress. We identified differentially methylated positions (DMPs) associated with general trauma, sexual trauma, and war trauma in both mothers and newborns. No DMPs were associated with chronic stress. Sexual trauma was positively associated with epigenetic age acceleration across several epigenetic clocks in mothers. General trauma and war trauma were positively associated with newborn epigenetic age acceleration using the extrinsic epigenetic age clock. We tested the top DMPs for enrichment of DNase I hypersensitive sites (DHS) and found no enrichment in mothers. In newborns, top DMPs associated with war trauma were enriched for DHS in embryonic and foetal cell types. Finally, one of the top DMPs associated with war trauma in newborns also predicted birthweight, completing the cycle from maternal stress to DNA methylation to newborn health outcome. Our results indicate that maternal stress is associated with site-specific changes in DNAm and epigenetic age acceleration in both mothers and newborns

Associations between Maternal Psychosocial Stress, DNA Methylation, and Newborn Birthweight Identified by Investigating Methylation at Individual, Regional, and Genome Levels

Stress is known to affect health throughout life and into future generations, but the underlying molecular mechanisms are unknown. We tested the hypothesis that maternal psychosocial stress influences DNA methylation (DNAm), which in turn impacts newborn health outcomes. Specifically, we analyzed DNAm at individual, regional, and genome-wide levels in order to test for associations with maternal stress and newborn birthweight. Maternal venous blood and newborn cord blood were assayed for methylation at ~450,000 CpG sites (n = 24 and 22, respectively). Methylation was analyzed by examining CpG sites individually (epigenome-wide-association-study [EWAS]), as regional groups (variably methylated region [VMR] analysis in maternal blood only), and through epigenome-wide measures (genome-wide mean methylation [GMM], Horvath’s epigenetic clock, and mitotic age). These methylation measures were tested for association with three measures of maternal stress (maternal war trauma, chronic stress, and experience of sexual violence) and one health outcome (newborn birthweight). We observed that maternal experiences of war trauma, chronic stress, and sexual assault were each associated with decreased newborn birthweight (p-value \u3c 1.95x10-7 in all cases). Testing individual CpG sites using EWAS, we observed no associations between DNAm and any measure of maternal stress or newborn birthweight in either maternal or cord blood after Bonferroni multiple testing correction, although the top ranked CpG site in maternal blood that associated with maternal chronic stress and sexual violence before multiple testing correction is located near the SPON1 gene. Testing at a regional level, we found increased methylation of a VMR in maternal blood near SPON1 that was associated with chronic stress and sexual violence after Bonferroni multiple testing correction (p-value = 1.95x10-7 and 8.3x10-6, respectively). At the epigenomic level, cord blood GMM was associated with significantly higher levels of war trauma (p-value 0.025) and suggestively associated with sexual violence (p-value = 0.053). The other two epigenome-wide measures were not associated with maternal stress or newborn birthweight in either tissue type. Despite our small sample size, we identified associations even after conservative multiple testing correction. Specifically, we found associations between DNAm and the three measures of maternal stress across both tissues, specifically a VMR in maternal blood and GMM in cord blood were both associated with different measures of maternal stress. The association of cord blood GMM, but not maternal blood GMM, with maternal stress may suggest different responses to stress in mother and newborn. It is noteworthy that we only found associations when CpG sites were analyzed in aggregate, either as variably methylation regions (VMRs) or a broad summary measure of genome-wide mean methylation (GMM)