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A bidirectional communication exists between the brain and the gut, in which the gut microbiota influences cognitive function and vice-versa. Gut dysbiosis has been linked to several diseases, including Alzheimer’s disease and related dementias (ADRD). However, the relationship between gut dysbiosis and markers of cerebral small vessel disease (cSVD), a major contributor to ADRD, is unknown. In this cross-sectional study, we examined the connection between the gut microbiome, cognitive, and neuroimaging markers of cSVD in the Framingham Heart Study (FHS). Markers of cSVD included white matter hyperintensities (WMH), peak width of skeletonized mean diffusivity (PSMD), and executive function (EF), estimated as the difference between the trail-making tests B and A. We included 972 FHS participants with MRI scans, neurocognitive measures, and stool samples and quantified the gut microbiota composition using 16S rRNA sequencing. We used multivariable association and differential abundance analyses adjusting for age, sex, BMI, and education level to estimate the association between gut microbiota and WMH, PSMD, and EF measures. Our results suggest an increased abundance of Pseudobutyrivibrio and Ruminococcus genera was associated with lower WMH and PSMD (p-values < 0.001), as well as better executive function (p-values < 0.01). In addition, in both differential and multivariable analyses, we found that the gram-negative bacterium Barnesiella intestinihominis was strongly associated with markers indicating a higher cSVD burden. Finally, functional analyses using PICRUSt implicated various KEGG pathways, including microbial quorum sensing, AMP/GMP-activated protein kinase, phenylpyruvate, and β-hydroxybutyrate production previously associated with cognitive performance and dementia. Our study provides important insights into the association between the gut microbiome and cSVD, but further studies are needed to replicate the findings.

Reported associations between leukocyte telomere length (LTL) attrition, diet and cardiovascular disease (CVD) are inconsistent. This study explores effects of prolonged exposure to a high cholesterol high fat (HCHF) diet on LTL in a baboon model of atherosclerosis. We measured LTL by qPCR in pedigreed baboons fed a chow (n = 105) or HCHF (n = 106) diet for 2 years, tested for effects of diet on LTL, and association between CVD risk factors and atherosclerotic lesions with LTL. Though not different at baseline, after 2 years median LTL is shorter in HCHF fed baboons (P 2 = 0.27, P = 0.027) and after 2 years (h2 = 0.46, P = 0.0038), baseline LTL does not predict lesion extent after 2 years. Atherogenic diet influences LTL, and LTL is a potential biomarker for early atherosclerosis. Prolonged exposure to an atherogenic diet decreases LTL and increases LTL attrition, and shortened LTL is associated with early-stage atherosclerosis in pedigreed baboons.

Patterns of genetic variation and covariation impact the evolution of the craniofacial complex and contribute to clinically significant malocclusions in modern human populations. Previous quantitative genetic studies have estimated the heritabilities and genetic correlations of skeletal and dental traits in humans and nonhuman primates, but none have estimated these quantitative genetic parameters across the dentognathic complex. A large and powerful pedigree from the Jirel population of Nepal was leveraged to estimate heritabilities and genetic correlations in 62 maxillary and mandibular arch dimensions, incisor and canine lengths, and post-canine tooth crown areas (N ≥ 739). Quantitative genetic parameter estimation was performed using maximum likelihood-based variance decomposition. Residual heritability estimates were significant for all traits, ranging from 0.269 to 0.898. Genetic correlations were positive for all trait pairs. Principal components analyses of the phenotypic and genetic correlation matrices indicate an overall size effect across all measurements on the first principal component. Additional principal components demonstrate positive relationships between post-canine tooth crown areas and arch lengths and negative relationships between post-canine tooth crown areas and arch widths, and between arch lengths and arch widths. Based on these findings, morphological variation in the human dentognathic complex may be constrained by genetic relationships between dental dimensions and arch lengths, with weaker genetic correlations between these traits and arch widths allowing for variation in arch shape. The patterns identified are expected to have impacted the evolution of the dentognathic complex and its genetic architecture as well as the prevalence of dental crowding in modern human populations.

Background: The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease is of fundamental importance given its global health and economic burden. Inhibition of ANGPTL3 (angiopoietin-like 3) has demonstrated a cardioprotective effect, showing promise for atherosclerotic cardiovascular disease treatment, and is currently the focus of ongoing clinical trials. Here, we assessed the genetic basis of variation in ANGPTL3 levels in the San Antonio Family Heart Study. Methods: We assayed ANGPTL3 protein levels in ≈1000 Mexican Americans from extended pedigrees. By drawing upon existing plasma lipidome profiles and genomic data we conducted analyses to understand the genetic basis to variation in ANGPTL3 protein levels, and accordingly the correlation with the plasma lipidome. Results: In a variance components framework, we identified that variation in ANGPTL3 was significantly heritable (h 2 =0.33, P =1.31×10 −16 ). To explore the genetic basis of this heritability, we conducted a genome-wide linkage scan and identified significant linkage (logarithm of odds =6.18) to a locus on chromosome 1 at 90 centimorgans, corresponding to the ANGPTL3 gene location. In the genomes of 23 individuals from a single pedigree, we identified a loss-of-function variant, rs398122988 (N121Kfs*2), in ANGPTL3 , that was significantly associated with lower ANGPTL3 levels (β=−1.69 SD units, P =3.367×10 −13 ), and accounted for the linkage signal at this locus. Given the known role of ANGPTL3 as an inhibitor of endothelial and lipoprotein lipase, we explored the association of ANGPTL3 protein levels and rs398122988 with the plasma lipidome and related phenotypes, identifying novel associations with phosphatidylinositols. Conclusions: Variation in ANGPTL3 protein levels is heritable and under significant genetic control. Both ANGPTL3 levels and loss-of-function variants in ANGPTL3 have significant associations with the plasma lipidome. These findings further our understanding of ANGPTL3 as a therapeutic target for atherosclerotic cardiovascular disease.

The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolic-related disorders and spur ongoing research of drug targets along this pathway.

Sickle cell disease (SCD) is the most common monogenic disorder in the world. Notably, there is extensive clinical heterogeneity in SCD that cannot be fully accounted for by known factors, and in particular, the extent to which the phenotypic diversity of SCD can be explained by genetic variation has not been reliably quantified. Here, in a family-based cohort of 449 patients with SCD and 755 relatives, we first show that 5 known modifiers affect 11 adverse outcomes in SCD to varying degrees. We then utilize a restricted maximum likelihood procedure to estimate the heritability of 20 hematologic traits, including fetal hemoglobin (HbF) and white blood cell count (WBC), in the clinically relevant context of inheritance from healthy carriers to SCD patients. We report novel estimations of heritability for HbF at 31.6% (±5.4%) and WBC at 41.2% (±6.8%) in our cohort. Finally, we demonstrate shared genetic bases between HbF, WBC, and other hematologic traits, but surprisingly little overlap between HbF and WBC themselves. In total, our analyses show that HbF and WBC have significant heritable components among individuals with SCD and their relatives, demonstrating the value of using family-based studies to better understand modifiers of SCD.

BACKGROUND: The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease (ASCVD) is of fundamental importance given its global health and economic burden. Inhibition of angiopoietin-like 3 (ANGPTL3) has demonstrated a cardioprotective effect, showing promise for ASCVD treatment, and is currently the focus of ongoing clinical trials. Here we assessed the genetic basis of variation in ANGPTL3 levels in the San Antonio Family Heart Study. METHODS: We assayed ANGPTL3 protein levels in ~1,000 Mexican Americans from extended pedigrees. By drawing upon existing plasma lipidome profiles and genomic data we conducted analyses to understand the genetic basis to variation in ANGPTL3 protein levels, and accordingly the correlation with the plasma lipidome. RESULTS: In a variance components framework we identified that variation in ANGPTL3 was significantly heritable (h(2)=0.33, P=1.31×10(−16)). To explore the genetic basis of this heritability, we conducted a genome-wide linkage scan and identified significant linkage (LOD = 6.18) to a locus on chromosome 1 at 90 cM, corresponding to the ANGPTL3 gene location. In the genomes of 23 individuals from a single pedigree, we identified a loss of function (LoF) variant, rs398122988 (N121Kfs*2), in ANGPTL3, that was significantly associated with lower ANGPTL3 levels (β=−1.69 SDU, P=3.367×10(−13)), and accounted for the linkage signal at this locus. Given the known role of ANGPTL3 as an inhibitor of endothelial and lipoprotein lipase we explored the association of ANGPTL3 protein levels and rs398122988 with the plasma lipidome and related phenotypes, identifying novel associations with phosphatidylinositols. CONCLUSIONS: Variation in ANGPTL3 protein levels is heritable and under significant genetic control. Both ANGPTL3 levels and LoF variants in ANGPTL3 have significant associations with the plasma lipidome. These findings further our understanding of ANGPTL3 as a therapeutic target for ASCVD.

Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2–189) 60% female; mean age = 42.58 years, range = 18–97 years, sd = 15.75 years] with no exclusion criteria for any given psychiatric disorder. We observed that total esterified cholesterol measured at the time of psychiatric assessment shared a significant genetic overlap with risk for suicide attempt (ρ(g) = −0.64, p = 1.24 × 10(−04)). We also found that total unesterified cholesterol measured around 20 years prior to assessment varied as a function of genetic proximity to an affected individual (h(2) = 0.21, se = 0.10, p = 8.73 × 10(−04); β(suicide) = −0.70, se = 0.25, p = 8.90 × 10(−03)). Finally, we found that the relationship between total unesterified cholesterol and suicide risk was significantly mediated by ABCA-1-specific cholesterol efflux capacity (β(suicide-efflux) = −0.45, p = 0.039; β(efflux-cholexterol) = −0.34, p

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Background Differential plasma concentrations of circulating lipid species are associated with pathogenesis of type 2 diabetes (T2D). Whether the wide inter-individual variability in the plasma lipidome contributes to the genetic basis of T2D is unknown. Here, we investigated the potential overlap in the genetic basis of the plasma lipidome and T2D-related traits. Results We used plasma lipidomic data (1202 pedigreed individuals, 319 lipid species representing 23 lipid classes) from San Antonio Family Heart Study in Mexican Americans. Bivariate trait analyses were used to estimate the genetic and environmental correlation of all lipid species with three T2D-related traits: risk of T2D, presence of prediabetes and homeostatic model of assessment – insulin resistance. We found that 44 lipid species were significantly genetically correlated with one or more of the three T2D-related traits. Majority of these lipid species belonged to the diacylglycerol (DAG, 17 species) and triacylglycerol (TAG, 17 species) classes. Six lipid species (all belonging to the triacylglycerol class and containing palmitate at the first position) were significantly genetically correlated with all the T2D-related traits. Conclusions Our results imply that: a) not all plasma lipid species are genetically informative for T2D pathogenesis; b) the DAG and TAG lipid classes partially share genetic basis of T2D; and c) 1-palmitate containing TAGs may provide additional insights into the genetic basis of T2D. Electronic supplementary material The online version of this article (doi:10.1186/s12863-017-0515-5) contains supplementary material, which is available to authorized users.

The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolic-related disorders and spur ongoing research of drug targets along this pathway.

Atherosclerotic plaques are characterized by an accumulation of macrophages, lipids, smooth muscle cells, and fibroblasts, and, in advanced stages, necrotic debris within the arterial walls. Dietary habits such as high fat and high cholesterol (HFHC) consumption are known risk factors for atherosclerosis. However, the key metabolic contributors to diet-induced atherosclerosis are far from established. Herein, we investigate the role of a 2-year HFHC diet challenge in the metabolic changes of development and progression of atherosclerosis. We used a non-human primate (NHP) model (baboons, n = 60) fed a HFHC diet for two years and compared metabolomic profiles in serum from animals on baseline chow with serum collected after the challenge diet using two-dimensional gas chromatography time-of-flight mass-spectrometry (2D GC-ToF-MS) for untargeted metabolomic analysis, to quantify metabolites that contribute to atherosclerotic lesion formation. Further, clinical biomarkers associated with atherosclerosis, lipoprotein measures, fat indices, and arterial plaque formation (lesions) were quantified. Using two chemical derivatization (i.e., silylation) approaches, we quantified 321 metabolites belonging to 66 different metabolic pathways, which revealed significantly different metabolic profiles of HFHC diet and chow diet fed baboon sera. We found heritability of two important metabolites, lactic acid and asparagine, in the context of diet-induced metabolic changes. In addition, abundance of cholesterol, lactic acid, and asparagine were sex-dependent. Finally, 35 metabolites correlated (R2, 0.068–0.271, P < 0.05) with total lesion burden assessed in three arteries (aortic arch, common iliac artery, and descending aorta) which could serve as potential biomarkers pending further validation. This study demonstrates the feasibility of detecting sex-specific and heritable metabolites in NHPs with diet-induced atherosclerosis using untargeted metabolomics allowing understanding of atherosclerotic disease progression in humans.

Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.

Folding of the primate brain cortex allows for improved neural processing power by increasing cortical surface area for the allocation of neurons. The arrangement of folds (sulci) and ridges (gyri) across the cerebral cortex is thought to reflect the underlying neural network. Gyrification, an adaptive trait with a unique evolutionary history, is affected by genetic factors different from those affecting brain volume. Using a large pedigreed population of ∼1000 Papio baboons, we address critical questions about the genetic architecture of primate brain folding, the interplay between genetics, brain anatomy, development, patterns of cortical–cortical connectivity, and gyrification’s potential for future evolution. Through Mantel testing and cluster analyses, we find that the baboon cortex is quite evolvable, with high integration between the genotype and phenotype. We further find significantly similar partitioning of variation between cortical development, anatomy, and connectivity, supporting the predictions of tension-based models for sulcal development. We identify a significant, moderate degree of genetic control over variation in sulcal length, with gyrus-shape features being more susceptible to environmental effects. Finally, through QTL mapping, we identify novel chromosomal regions affecting variation in brain folding. The most significant QTL contain compelling candidate genes, including gene clusters associated with Williams and Down syndromes. The QTL distribution suggests a complex genetic architecture for gyrification with both polygeny and pleiotropy. Our results provide a solid preliminary characterization of the genetic basis of primate brain folding, a unique and biomedically relevant phenotype with significant implications in primate brain evolution.

This study presents quantitative ultrasonography (QUS) bone quality data for an underrepresented, south Asian pediatric population from Nepal. Data were collected as part of a longitudinal study of growth and development. This study offers normative data and documents the effect of stunting, wasting, and underweight on the bone properties measured by QUS.The purpose of this study was to (1) examine the bone quality of a rural, non-Western pediatric population using QUS, (2) explore variation in the trajectory of bone quality development between males and females, and (3) examine the impact of growth disruption(s) on bone quality.A cross-sectional study of 860 children and adolescents aged 5-18 years from the Jirel ethnic group in eastern Nepal was performed. The Sunlight Omnisense 7000P was used to assess bone quality of the distal 1/3 radius and midshaft tibia. WHO reference standards were used to assess growth disruptions of height, weight, and BMI.QUS bone quality data for an underrepresented, non-Western pediatric population are presented for the radius and tibia. A sizable portion of the study participants were classified as stunted, wasted, and/or underweight. Despite this prevalence of growth disruption in the study sample, bone quality data conform to other documented populations with less growth disruption. Thus, this study offers normative data and documents the minimal effect of stunting, wasting, and underweight on the bone properties measured by QUS.Non-Western pediatric populations are significantly underserved with regard to simple, non-invasive screening tools that may help identify developmental disorders and assess bone health. The children and adolescents examined here represent normal growth and development for an underrepresented south Asian population. While this work demonstrates that stunting, wasting, or underweight status at time of QUS assessment is not associated with poor bone quality, we do suggest that further study is needed to examine possible cumulative effects of persistent disruptions that may lead to compromised bone quality in later adolescence.

Behavioral variation within and between populations and species of the genus Papio has been studied extensively, but little is known about the genetic causes of individual- or population-level differences. This study investigates the influence of genetic variation on personality (sometimes referred to as temperament) in baboons and identifies a candidate gene partially responsible for the variation in that phenotype. To accomplish these goals, we examined individual variation in response to both novel objects and an apparent novel social partner (using a mirror test) among pedigreed baboons (n = 578) from the Southwest National Primate Research Center. We investigated the frequency and duration of individual behaviors in response to novel objects and used multivariate factor analysis to identify trait-like dimensions of personality. Exploratory factor analysis identified two distinct dimensions of personality within this population. Factor 1 accounts for 46.8 % of the variance within the behavioral matrix, and consists primarily of behaviors related to the "boldness" of the subject. Factor 2 accounts for 18.8 % of the variation, and contains several "anxiety" like behaviors. Several specific behaviors, and the two personality factors, were significantly heritable, with the factors showing higher heritability than most individual behaviors. Subsequent analyses show that the behavioral reactions observed in the test protocol are associated with animals' social behavior observed later in their home social groups. Finally we used linkage analysis to map quantitative trait loci for the measured phenotypes. Single nucleotide polymorphisms in a positional candidate gene (SNAP25) are associated with variation in one of the personality factors, and CSF levels of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. This study documents heritable variation in personality among baboons and suggests that sequence variation in SNAP25 may influence differences in behavior and neurochemistry in these nonhuman primates.

Only few systematic studies on the contribution of copy number variation to gene expression variation have been published to date. Here we identify effects of copy number variable regions (CNVRs) on nearby gene expression by investigating 909 CNVRs and expression levels of 12059 nearby genes in white blood cells from Mexican-American participants of the San Antonio Family Heart Study. We empirically evaluate our ability to detect the contribution of CNVs to proximal gene expression (presumably in cis) at various window sizes (up to a 10 Mb distance) between the gene and CNV. We found a ~1-Mb window size to be optimal for capturing cis effects of CNVs. Up to 10% of the CNVs in this study were found to be significantly associated with the expression of at least one gene within their vicinity. As expected, we find that CNVs that directly overlap gene sequences have the largest effects on gene expression (compared with non-overlapping CNVRs located nearby), with positive correlation (except for a few exceptions) between estimated genomic dosage and expression level. We find that genes whose expression level is significantly influenced by nearby CNVRs are enriched for immunity and autoimmunity related genes. These findings add to the currently limited catalog of CNVRs that are recognized as expression quantitative trait loci, and have implications for future study designs as well as for prioritizing candidate causal variants in genomic regions associated with disease.

Background— Cardiovascular disease (CVD) is the most common cause of death in the United States and is associated with a high economic burden. Prevention of CVD focuses on controlling or improving the lipid profile of patients at risk. The human lipidome is made up of thousands of ubiquitous lipid species. By studying biologically simple canonical lipid species, we investigated whether the lipidome is genetically redundant and whether its genetic influences can provide clinically relevant clues of CVD risk. Methods and Results— We performed a genetic study of the human lipidome in 1212 individuals from 42 extended Mexican American families. High-throughput mass spectrometry enabled rapid capture of precise lipidomic profiles, providing 319 unique species. Using variance component–based heritability analyses and bivariate trait analyses, we detected significant genetic influences on each lipid assayed. Median heritability of the plasma lipid species was 0.37. Hierarchical clustering based on complex genetic correlation patterns identified 12 genetic clusters that characterized the plasma lipidome. These genetic clusters were differentially but consistently associated with risk factors of CVD, including central obesity, obesity, type 2 diabetes mellitus, raised serum triglycerides, and metabolic syndrome. Also, these clusters consistently predicted occurrence of cardiovascular deaths during follow-up. Conclusions— The human plasma lipidome is heritable. Shared genetic influences reduce the dimensionality of the human lipidome into clusters that are associated with risk factors of CVD.

Objectives: Determining the genetic architecture of quantitative traits and genetic correlations among them is important for understanding morphological evolution patterns. We address two questions regarding papionin evolution: (1) what effect do body and cranial size, age, and sex have on phenotypic (VP) and additive genetic (VA) variation in baboon crania, and (2) how might additive genetic correlations between craniofacial traits and body mass affect morphological evolution? Materials and Methods: We use a large captive pedigreed baboon sample to estimate quantitative genetic parameters for craniofacial dimensions (EIDs). Our models include nested combinations of the covariates listed above. We also simulate the correlated response of a given EID due to selection on body mass alone. Results: Covariates account for 1.2-91% of craniofacial VP. EID VA decreases across models as more covariates are included. The median genetic correlation estimate between each EID and body mass is 0.33. Analysis of the multivariate response to selection reveals that observed patterns of craniofacial variation in extant baboons cannot be attributed solely to correlated response to selection on body mass, particularly in males. Discussion: Because a relatively large proportion of EID VA is shared with body mass variation, different methods of correcting for allometry by statistically controlling for size can alter residual VP patterns. This may conflate direct selection effects on craniofacial variation with those resulting from a correlated response to body mass selection. This shared genetic variation may partially explain how selection for increased body mass in two different papionin lineages produced remarkably similar craniofacial phenotypes.

Background The purpose of this study was to determine whether dietary manipulation can reliably induce early-stage atherosclerosis and clinically relevant changes in vascular function in an established, well-characterized non-human primate model. Methods We fed 112 baboons a high-cholesterol, high-fat challenge diet for two years. We assayed circulating biomarkers of cardiovascular disease (CVD) risk, at 0, 7, and 104 weeks into the challenge; assessed arterial compliance noninvasively at 104 weeks; and measured atherosclerotic lesions in three major arteries at necropsy. Results We observed evidence of atherosclerosis in all but one baboon fed the two-year challenge diet. CVD risk biomarkers, the prevalence, size, and complexity of arterial lesions, plus consequent arterial stiffness, were increased in comparison with dietary control animals. Conclusions Feeding baboons a high-cholesterol, high-fat diet for two years reliably induces atherosclerosis, with risk factor profiles, arterial lesions, and changes in vascular function also seen in humans.

Plasma lipidome is now increasingly recognized as a potentially important marker of chronic diseases, but the exact extent of its contribution to the interindividual phenotypic variability in family studies is unknown. Here, we used the rich data from the ongoing San Antonio Family Heart Study (SAFHS) and developed a novel statistical approach to quantify the independent and additive value of the plasma lipidome in explaining metabolic syndrome (MS) variability in Mexican American families recruited in the SAFHS. Our analytical approach included two preprocessing steps: principal components analysis of the high-resolution plasma lipidomics data and construction of a subject-subject lipidomic similarity matrix. We then used the Sequential Oligogenic Linkage Analysis Routines software to model the complex family relationships, lipidomic similarities, and other important covariates in a variance components framework. Our results suggested that even after accounting for the shared genetic influences, indicators of lipemic status (total serum cholesterol, TGs, and HDL cholesterol), and obesity, the plasma lipidome independently explained 22% of variability in the homeostatic model of assessment-insulin resistance trait and 16% to 22% variability in glucose, insulin, and waist circumference. Our results demonstrate that plasma lipidomic studies can additively contribute to an understanding of the interindividual variability in MS.

Objective Waist circumference (WC), the clinical marker of central obesity, is gaining popularity as a screening tool for type 2 diabetes (T2D). While there is epidemiologic evidence favoring the WC-T2D association, its biological substantiation is generally weak. Our objective was to determine the independent association of plasma lipid repertoire with WC. Methods Samples and data from the San Antonio Family Heart Study of 1208 Mexican Americans from 42 extended families were used. Association of plasma lipidomic profiles with the cross-sectionally assessed WC was determined. Plasma lipidomic profiling entailed liquid chromatography with mass spectrometry. Statistical analyses included multivariable polygenic regression models and bivariate trait analyses using the SOLAR software. Results After adjusting for age and sex interactions, body mass index, homeostasis model of assessment—insulin resistance, total cholesterol, triglycerides, high density lipoproteins and use of lipid lowering drugs, dihydroceramides as a class were associated with WC. Dihydroceramide species 18:0, 20:0, 22:0, and 24:1 were significantly associated and genetically correlated with WC. Two sphingomyelin species (31:1 and 41:1) were also associated with WC. Conclusions Plasma dihydroceramide levels independently associate with WC. Thus, high resolution plasma lipidomic studies can provide further credence to the biological underpinnings of the association of WC with T2D.

Intracortical microstructure influences crack propagation and arrest within bone cortex. Genetic variation in intracortical remodeling may contribute to mechanical integrity and, therefore, fracture risk. Our aim was to determine the degree to which normal population-level variation in intracortical microstructure is due to genetic variation. We examined right femurs from 101 baboons (74 females, 27 males; aged 7–33 years) from a single, extended pedigree to determine osteon number, osteon area (On.Ar), haversian canal area, osteon population density, percent osteonal bone (%On.B), wall thickness (W.Th), and cortical porosity (Ct.Po). Through evaluation of the covariance in intracortical properties between pairs of relatives, we quantified the contribution of additive genetic effects (heritability [h 2]) to variation in these traits using a variance decomposition approach. Significant age and sex effects account for 9 % (Ct.Po) to 21 % (W.Th) of intracortical microstructural variation. After accounting for age and sex, significant genetic effects are evident for On.Ar (h 2 = 0.79, p = 0.002), %On.B (h 2 = 0.82, p = 0.003), and W.Th (h 2 = 0.61, p = 0.013), indicating that 61–82 % of the residual variation (after accounting for age and sex effects) is due to additive genetic effects. This corresponds to 48–75 % of the total phenotypic variance. Our results demonstrate that normal, population-level variation in cortical microstructure is significantly influenced by genes. As a critical mediator of crack behavior in bone cortex, intracortical microstructural variation provides another mechanism through which genetic variation may affect fracture risk.

Objective: Type 2 diabetes (T2DM) is a complex metabolic disease and is more prevalent in certain ethnic groups such as the Mexican Americans. The goal of our study was to perform a genome-wide linkage (GWL) analysis to localize T2DM susceptibility loci in Mexican Americans. Methods: We used the phenotypic and genotypic data from 1,122 Mexican-American individuals (307 families) who participated in the Veterans Administration Genetic Epidemiology Study (VAGES). GWL analysis was performed using the variance components approach. Data from 2 additional Mexican-American family studies, the San Antonio Family Heart Study (SAFHS) and the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), were combined with the VAGES data to test for improved linkage evidence. Results: After adjusting for covariate effects, T2DM was found to be under significant genetic influences (h2 = 0.62, p = 2.7 × 10-6). The strongest evidence for linkage of T2DM occurred between markers D9S1871 and D9S2169 on chromosome 9p24.2-p24.1 (LOD = 1.8). Given that we previously reported suggestive evidence for linkage of T2DM at this region also in SAFDGS, we found the significant and increased linkage evidence (LOD = 4.3, empirical p = 1.0 × 10-5, genome-wide p = 1.6 × 10-3) for T2DM at the same chromosomal region, when we performed a GWL analysis of the VAGES data combined with the SAFHS and SAFDGS data. Conclusion: Significant T2DM linkage evidence was found on chromosome 9p24 in Mexican Americans. Importantly, the chromosomal region of interest in this study overlaps with several recent genome-wide association studies involving T2DM-related traits. Given its overlap with such findings and our own initial T2DM association findings in the 9p24 chromosomal region, high throughput sequencing of the linked chromosomal region could identify the potential causal T2DM genes.

Developmental genetics research on mice provides a relatively sound understanding of the genes necessary and sufficient to make mammalian teeth. However, mouse dentitions are highly derived compared with human dentitions, complicating the application of these insights to human biology. We used quantitative genetic analyses of data from living nonhuman primates and extensive osteological and paleontological collections to refine our assessment of dental phenotypes so that they better represent how the underlying genetic mechanisms actually influence anatomical variation. We identify ratios that better characterize the output of two dental genetic patterning mechanisms for primate dentitions. These two newly defined phenotypes are heritable with no measurable pleiotropic effects. When we consider how these two phenotypes vary across neontological and paleontological datasets, we find that the major Middle Miocene taxonomic shift in primate diversity is characterized by a shift in these two genetic outputs. Our results build on the mouse model by combining quantitative genetics and paleontology, and thereby elucidate how genetic mechanisms likely underlie major events in primate evolution.

Aims The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Methods and results Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. Conclusion We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies.

Background There is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (≥95 cm in males and ≥80 cm in females) combined with high serum triglyceride concentration (≥2.0 mmol/L in males and ≥1.5 mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease. However, the prevalence of this phenotype in high-risk populations, its association with T2D, and the genetic or epigenetic influences on HTGW are not well explored. Using data from large, extended families of Mexican Americans (a high-risk minority population in the USA) we aimed to: (1) estimate the prevalence of this phenotype, (2) test its association with T2D and related traits, and (3) dissect out the genetic and epigenetic associations with this phenotype using genome-wide and epigenome-wide studies, respectively. Results Data for this study was from 850 Mexican American participants (representing 39 families) recruited under the ongoing San Antonio Family Heart Study, 26 % of these individuals had HTGW. This phenotype was significantly heritable (h2r = 0.52, p = 1.1 × 10−5) and independently associated with T2D as well as fasting glucose levels and insulin resistance. We conducted genome-wide association analyses using 759,809 single nucleotide polymorphisms (SNPs) and epigenome-wide association analyses using 457,331 CpG sites. There was no evidence of any SNP associated with HTGW at the genome-wide level but two CpG sites (cg00574958 and cg17058475) in CPT1A and one CpG site (cg06500161) in ABCG1 were significantly associated with HTGW and remained significant after adjusting for the closely related components of metabolic syndrome. CPT1A holds a cardinal position in the metabolism of long-chain fatty acids while ABCG1 plays a role in triglyceride metabolism. Conclusions Our results reemphasize the value of HTGW as a marker of T2D. This phenotype shows association with DNA methylation within CPT1A and ABCG1, genes involved in fatty acid and triglyceride metabolism. Our results underscore the importance of epigenetics in a clinically informative phenotype. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0173-x) contains supplementary material, which is available to authorized users.

SLC30A8encodes zinc transporter 8 which is involved in packaging and release of insulin. Evidence for the association ofSLC30A8variants with type 2 diabetes (T2D) is inconclusive. We interrogated single nucleotide polymorphisms (SNPs) aroundSLC30A8for association with T2D in high-risk, pedigreed individuals from extended Mexican American families. This study of 118 SNPs within 50 kb of theSLC30A8locus tested the association with eight T2D-related traits at four levels: (i) each SNP using measured genotype approach (MGA); (ii) interaction of SNPs with age and sex; (iii) combinations of SNPs using Bayesian Quantitative Trait Nucleotide (BQTN) analyses; and (iv) entire gene locus using the gene burden test. Only one SNP (rs7817754) was significantly associated with incident T2D but a summary statistic based on all T2D-related traits identified 11 novel SNPs. Three SNPs and one SNP were weakly but interactively associated with age and sex, respectively. BQTN analyses could not demonstrate any informative combination of SNPs over MGA. Lastly, gene burden test results showed that at best theSLC30A8locus could account for only 1-2% of the variability in T2D-related traits. Our results indicate a lack of association of theSLC30A8SNPs with T2D in Mexican American families.

Individual differences in biological ageing (i.e., the rate of physiological response to the passage of time) may be due in part to genotype-specific variation in gene action. However, the sources of heritable variation in human age-related gene expression profiles are largely unknown. We have profiled genome-wide expression in peripheral blood mononuclear cells from 1240 individuals in large families and found 4472 human autosomal transcripts, representing ∼4349 genes, significantly correlated with age. We identified 623 transcripts that show genotype by age interaction in addition to a main effect of age, defining a large set of novel candidates for characterization of the mechanisms of differential biological ageing. We applied a novel SNP genotype × age interaction test to one of these candidates, the ubiquilin-like gene UBQLNL , and found evidence of joint cis -association and genotype by age interaction as well as trans -genotype by age interaction for UBQLNL expression. Both UBQLNL expression levels at recruitment and cis genotype are associated with longitudinal cancer risk in our study cohort.

Several measures of lipoprotein phenotype are significant predictors of cardiovascular risk. Although such lipoprotein phenotypes are under strong genetic control, it is not clear to what extent they are controlled by the same - and by different - genes and whether these relationships may be altered in different dietary environments. Therefore, we measured six lipoprotein traits (three LDL traits - LDLC and apoB concentrations and LDL size - and three HDL traits - HDLC and apoA1 concentrations and HDL size) on each of three diets differing in level of fat and cholesterol. In bivariate analyses, all but two metabolically related trait pairs were genetically correlated, though none were completely correlated, implying additive genetic effects by both pleiotropic and unique genes. In comparing genetic correlations for the same pair of traits across diet, we detected evidence of diet effects on genetic control of these metabolically related traits; specifically, increasing level of dietary cholesterol was associated with a significant decrease in the genetic correlation of apoA1 with HDL size, and a significant increase in the genetic correlations of LDL size with LDLC and apoB. The results suggest a complex network of genes affecting lipoprotein metabolism: the genes may exert both unique and pleiotropic effects; the genes may exert detectable effects in many or only in specific dietary environments.

The clinical spectrum of tooth-eruption disorders includes both syndromic and nonsyndromic problems ranging from delayed eruption to a complete failure of eruption. A defect in the differential apposition/resorption mechanism in alveolar bone can cause conditions, such as tooth ankylosis, primary failure of eruption (PFE), failure of eruption caused by inadequate arch length, and canine impaction. As our knowledge of the molecular events underlying normal tooth eruption has increased, so too has our understanding of clinical eruption disorders. The recent finding that one gene, parathyroid hormone receptor 1 ( PTH1R ), is causative for familial cases of PFE suggests that other disturbances in tooth eruption may have a genetic etiology. In this report, we evaluated the current terminology (ie, ankylosis, PFE, secondary retention) used to describe nonsyndromic eruption disorders, in light of this genetic discovery. We observed that some patients previously diagnosed with ankylosis were subsequently found to have alterations in the PTH1R gene, indicating the initial misdiagnosis of ankylosis and the necessary reclassification of PFE. We further investigated the relationship of the PTH1R gene, by using a network pathway analysis, to determine its connectivity to previously identified genes that are critical to normal tooth eruption. We found that PTH1R acts in a pathway with genes, such as parathyroid hormone related peptide ( PTHrP ), that have been shown to be important in bone remodeling, hence eruption, in a rat model. Thus, recent advances in our understanding of normal and abnormal tooth eruption should allow us in the future to develop a clinical nomenclature system that is determined more by the molecular genetic cause of the eruption failures versus the clinical appearance of the various eruption disorders.

Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD).Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P≈.00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM.Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.