Daniela Zanetti

Genetic risk score of NOS gene variants associated with myocardial infarction correlates with coronary incidence across Europe

Coronary artery disease (CAD) mortality and morbidity is present in the European continent in a four-fold gradient across populations, from the South (Spain and France) with the lowest CAD mortality, towards the North (Finland and UK). This observed gradient has not been fully explained by classical or single genetic risk factors, resulting in some cases in the so called Southern European or Mediterranean paradox. Here we approached population genetic risk estimates using genetic risk scores (GRS) constructed with single nucleotide polymorphisms (SNP) from nitric oxide synthases (NOS) genes. These SNPs appeared to be associated with myocardial infarction (MI) in 2165 cases and 2153 controls. The GRSs were computed in 34 general European populations. Although the contribution of these GRS was lower than 1% between cases and controls, the mean GRS per population was positively correlated with coronary incidence explaining 65–85% of the variation among populations (67% in women and 86% in men). This large contribution to CAD incidence variation among populations might be a result of colinearity with several other common genetic and environmental factors. These results are not consistent with the cardiovascular Mediterranean paradox for genetics and support a CAD genetic architecture mainly based on combinations of common genetic polymorphisms. Population genetic risk scores is a promising approach in public health interventions to develop lifestyle programs and prevent intermediate risk factors in certain subpopulations with specific genetic predisposition.

Human Diversity in Jordan: Polymorphic Alu Insertions in General Jordanian and Bedouin Groups

ABSTRACT Jordan, located in the Levant region, is an area crucial for the investigation of human migration between Africa and Eurasia. However, the genetic history of Jordanians has yet to be clarified, including the origin of the Bedouins today resident in Jordan. Here, we provide new genetic data on autosomal independent markers in two Jordanian population samples (Bedouins and the general population) to begin to examine the genetic diversity inside this country and to provide new information about the genetic position of these populations in the context of the Mediterranean and Middle East area. The markers analyzed were 18 Alu polymorphic insertions characterized by their identity by descent, known ancestral state (lack of insertion), and apparent selective neutrality. The results indicate significant genetic differences between Bedouins and general Jordanians (p = 0.038). Whereas Bedouins show a close genetic proximity to North Africans, general Jordanians appear genetically more similar to other Middle East populations. In general, these data are consistent with the hypothesis that Bedouins had an important role in the peopling of Jordan and constitute the original substrate of the current population. However, migration into Jordan in recent years likely has contributed to the diversity among current Jordanian population groups.

Analysis of Genomic Regions Associated With Coronary Artery Disease Reveals Continent-Specific Single Nucleotide Polymorphisms in North African Populations

Background In recent years, several genomic regions have been robustly associated with coronary artery disease (CAD) in different genome-wide association studies (GWASs) conducted mainly in people of European descent. These kinds of data are lacking in African populations, even though heart diseases are a major cause of premature death and disability. Methods Here, 384 single nucleotide polymorphisms (SNPs) in the top four CAD risk regions (1p13, 1q41, 9p21, and 10q11) were genotyped in 274 case-control samples from Morocco and Tunisia, with the aim of analyzing for the first time if the associations found in European populations were transferable to North Africans. Results The results indicate that, as in Europe, these four genetic regions are also important for CAD risk in North Africa. However, the individual SNPs associated with CAD in Africa are different from those identified in Europe in most cases (1p13, 1q41, and 9p21). Moreover, the seven risk variants identified in North Africans are efficient in discriminating between cases and controls in North African populations, but not in European populations. Conclusions This study indicates a disparity in markers associated to CAD susceptibility between North Africans and Europeans that may be related to population differences in the chromosomal architecture of these risk regions.

Genetic analyses in UK Biobank identifies 78 novel loci associated with urinary biomarkers providing new insights into the biology of kidney function and chronic disease

Background Urine biomarkers, such as creatinine, microalbumin, potassium and sodium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease and diabetes mellitus. Knowledge about the genetic determinants of the levels of these biomarker may shed light on pathophysiological mechanisms underlying the development of these diseases. Methods We performed genome-wide association studies of urinary levels of creatinine, microalbumin, potassium, and sodium in up to 326,441 unrelated individuals of European ancestry from the UK Biobank, a large population-based cohort study of over 500,000 individuals recruited across the United Kingdom in 2006-2010. Further, we explored genetic correlations, tissue-specific gene expression and possible causal genes related to these biomarkers. Results We identified 23 genome-wide significant independent loci associated with creatinine, 20 for microalbumin, 12 for potassium, and 38 for sodium. We confirmed several established associations including between the CUBN locus and microalbumin (rs141640975, p=3.11e-68). Variants associated with the levels of urinary creatinine, potassium, and sodium mapped to loci previously associated with obesity (GIPR, rs1800437, p=9.81e-10), caffeine metabolism (CYP1A1, rs2472297, p=1.61e-8) and triglycerides (GCKR, rs1260326, p=4.37e-16), respectively. We detected high pairwise genetic correlation between the levels of four urinary biomarkers, and significant genetic correlation between their levels and several anthropometric, cardiovascular, glycemic, lipid and kidney traits. We highlight GATM as causally implicated in the genetic control of urine creatinine, and GIPR, a potential diabetes drug target, as a plausible causal gene involved in regulation of urine creatinine and sodium. Conclusion We report 78 novel genome-wide significant associations with urinary levels of creatinine, microalbumin, potassium and sodium in the UK Biobank, confirming several previously established associations and providing new insights into the genetic basis of these traits and their connection to chronic diseases. Author Summary Urine biomarkers, such as creatinine, microalbumin, potassium and sodium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease and diabetes mellitus. Knowledge about the genetic determinants of the levels of these biomarker may shed light on pathophysiological mechanisms underlying the development of these diseases. Here, we performed genome-wide association studies of urinary levels of creatinine, microalbumin, potassium and sodium in up to 326,441 unrelated individuals of European ancestry from the UK Biobank. Further, we explored genetic correlations, tissue-specific gene expression and possible causal genes related to these biomarkers. We identified 78 novel genome-wide significant associations with urinary biomarkers, confirming several previously established associations and providing new insights into the genetic basis of these traits and their connection to chronic diseases. Further, we highlight GATM as causally implicated in the genetic control of urine creatinine, and GIPR, a potential diabetes drug target, as a plausible causal gene involved in regulation of urine creatinine and sodium. The knowledge arising from our work may improve the predictive utility of the respective biomarker and point to new therapeutic strategies to prevent common diseases.

Transethnic differences in GWAS signals: A simulation study

Genome‐wide association studies (GWASs) have allowed researchers to identify thousands of single nucleotide polymorphisms (SNPs) and other variants associated with particular complex traits. Previous studies have reported differences in the strength and even the direction of GWAS signals across different populations. These differences could be due to a combination of (1) lack of power, (2) allele frequency differences, (3) linkage disequilibrium (LD) differences, and (4) true differences in causal variant effect sizes.

A survey of sub-Saharan gene flow into the Mediterranean at risk loci for coronary artery disease

This study tries to find detectable signals of gene flow of Sub-Saharan origin into the Mediterranean in four genomic regions previously associated with coronary artery disease. A total of 366 single-nucleotide polymorphisms were genotyped in 772 individuals from 10 Mediterranean countries. Population structure analyses were performed, in which a noticeable Sub-Saharan component was found in the studied samples. The overall percentage of this Sub-Saharan component presents differences between the two Mediterranean coasts. D-statistics suggest possible Sub-Saharan introgression into one of the studied genomic regions (10q11). We also found differences in linkage disequilibrium patterns between the two Mediterranean coasts, possibly attributable to differential Sub-Saharan admixture. Our results confirm the potentially important role of human demographic history when performing epidemiological studies.

True causal effect size heterogeneity is required to explain trans-ethnic differences in GWAS signals

Through genome-wide association studies (GWASs), researchers have identified hundreds of genetic variants associated with particular complex traits. Previous studies have compared the pattern of association signals across different populations in real data, and these have detected differences in the strength and sometimes even the direction of GWAS signals. These differences could be due to a combination of (1) lack of power (insufficient sample sizes); (2) minor allele frequency (MAF) differences (again affecting power); (3) linkage disequilibrium (LD) differences (affecting power to ‘tag’ the causal variant); and (4) true differences in causal variant effect sizes (defined by relative risks). In the present work, we sought to assess whether the first three of these reasons are sufficient on their own to explain the observed incidence of trans-ethnic differences in replications of GWAS signals, or whether the fourth reason is also required. We simulated case-control data of European, Asian and African ancestry, drawing on observed MAF and LD patterns seen in the 1000-Genomes reference dataset and assuming the true causal relative risks were the same in all three populations. We found that a combination of Euro-centric SNP selection and between-population differences in LD, accentuated by the lower SNP density typical of older GWAS panels, was sufficient to explain the rate of trans-ethnic differences previously reported, without the need to assume between-population differences in true causal SNP effect size. This suggests a cross-population consistency that has implications for our understanding of the interplay between genetics and environment in the aetiology of complex human diseases.

X-Chromosome Alu Insertions in Bahía Blanca, Argentina: Assessment of Population Information from Varied Genetic Markers and Usefulness of X-Chromosome Markers to Trace Sex-Biased Parental Contributions

ABSTRACT Bahía Blanca is an urban city in a historically and geographically strategic location for the mixture of different populations in Argentina. In the present study, 10 Alu elements from the X chromosome are analyzed to characterize the genetic composition of the citys population, to compare it with other worldwide populations, and to explore the usefulness of X-chromosome markers for human population genetics purposes. In the Bahía Blanca sample, 7 of 10 Alu insertion frequencies are polymorphic. X-chromosome Alu results in Bahía Blanca are compared with eight different populations from Africa, Europe, and America. Genetic distance analysis indicates that the Bahía Blanca sample is closer to the European and North African samples (average distances of 0.106 and 0.113) than to the Native American (0.163) and sub-Saharan African samples (0.247). Genetic relationships shown by multidimensional scaling illustrate the intermediate position of Bahía Blanca compared with groups in other regions (European, Native American, and African). Admixture results of the Bahía Blanca sample for X-chromosome markers indicate similar proportions of Native American (0.472) and European parental contributions (0.479) and a minor sub-Saharan African contribution (0.049). These results are consistent with the past decades genetic studies of Argentinean populations that reported higher Native American and sub-Saharan African contributions than previous data.

Population structure from NOS genes correlates with geographical differences in coronary incidence across Europe.

OBJECTIVES The population analysis of cardiovascular risk and non-risk genetic variation can help to identify adaptive or random demographic processes that shaped coronary incidence variation across geography. MATERIAL AND METHODS In this study, 114 single nucleotide polymorphisms and 17 tandem repeat polymorphisms from Nitric Oxide Synthases (NOS) regions were analyzed in 1686 individuals from 35 populations from Europe, North Africa, and the Middle East. NOS genes encode for key enzymes on nitric oxide availability, which is involved in several cardiovascular processes. These genetic variations were used to test for selection and to infer the population structure of NOS regions. Moreover, we tested whether the variation in the incidence of coronary events and in the levels of classical risk factors in 11 of these European populations could be explained by the population structure estimates. RESULTS Our results supported, first, the absence of clear signs of selection for NOS genetic variants associated with cardiovascular diseases, and second, the presence of a continuous genetic pattern of variation across European and North African populations without a Mediterranean barrier for gene flow. Finally, population structure estimates from NOS regions are closely correlated with coronary event rates and classical risk parameters (explaining 39-98%) among European populations. CONCLUSION Our results reinforce the hypothesis that genetic bases of cardiovascular diseases and associated complex phenotypes could be geographically shaped by random demographic processes.

Population variation of LIN28B in the Mediterranean: Novel markers for microgeographic discrimination

The aim of this study is to determine whether the LIN28B gene is differentially distributed in the Mediterranean region through the analysis of the allele distribution of three single nucleotide polymorphisms (SNPs), namely rs7759938, rs314277, and rs221639, in 24 populations. These SNPs have been recently related to the age at menarche, pubertal height growth, peripubertal body mass index, levels of prenatal testosterone exposure, and cancer survival.