Professional Education

  • PhD in Population Genetics, University of Barcelona (2015)
  • Master of Experimental Biology, University of Cagliari (2011)
  • Bachelor of Biology, University of Cagliari (2009)

Stanford Advisors

All Publications

  • Alcohol use and cardiometabolic risk in the UK Biobank: A Mendelian randomization study. PloS one Lankester, J., Zanetti, D., Ingelsson, E., Assimes, T. L. 2021; 16 (8): e0255801


    Observational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization (MR) to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. Using the well-established ADH1B Arg47His variant (rs1229984) and up to 24 additional SNPs recently found to be associated with alcohol consumption in an independent dataset as instruments, we conducted two-stage least squares and inverse weighted variance MR analyses, both as one-sample analyses in the UK Biobank and as two-sample analyses in external consortia. In the UK Biobank inverse variance weighted analyses, we found that one additional drink of alcohol per day was positively associated with systolic blood pressure (beta = 2.65 mmHg [1.40, 3.89]), hemorrhagic stroke (OR = 2.25 [1.41, 3.60]), and atrial fibrillation (OR = 1.26 [1.07, 1.48]), which were replicated in multivariable analyses. Alcohol was also associated with all cardiovascular disease and all-cause death. A positive association with myocardial infarction did not replicate in multivariable analysis, with suggestive mediation through blood pressure; similarly, a positive association between alcohol use with type 2 diabetes was mitigated by BMI in multivariable analysis. Findings were generally null in replication with two-sample analyses. Alcohol was not protective for any disease outcome with any analysis method, dataset, or strata. Stratifications by sex and smoking in the UK Biobank revealed higher point estimates of risk for several outcomes for men and mixed results for smoking strata, but no statistically significant heterogeneity. Our results are consistent with an overall harmful and/or null effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy diet and lifestyle.

    View details for DOI 10.1371/journal.pone.0255801

    View details for PubMedID 34379647

  • Mendelian randomization and experimental IUGR reveal the adverse effect of low birth weight on lung structure and function. Scientific reports Kuiper-Makris, C., Zanetti, D., Vohlen, C., Fahle, L., Muller, M., Odenthal, M., Felderhoff-Muser, U., Dotsch, J., Alejandre Alcazar, M. A. 2020; 10 (1): 22395


    Intrauterine growth restriction (IUGR) and low birth weigth (LBW) are risk factors for neonatal chronic lung disease. However, maternal and fetal genetic factors and the molecular mechanisms remain unclear. We investigated the relationship between LBW and lung function with Mendelian randomisation analyses and studied angiogenesis in a low protein diet rat model of IUGR. Our data indicate a possible association between LBW and reduced FEV1 (p=5.69E-18, MR-PRESSO) and FVC (6.02E-22, MR-PRESSO). Complimentary, we demonstrated two-phased perinatal programming after IUGR. The intrauterine phase (embryonic day 21) is earmarked by a reduction of endothelial cell markers (e.g. CD31) as well as mRNA expression of angiogenic factors (e.g., Vegfa, Flt1, Klf4). Protein analysis identified an activation of anti-angiogenic mTOR effectors. In the postnatal phase, lung capillaries (<20m) were significantly reduced, expression of CD31 and VE-Cadherin were unaffected, whereas SMAD1/5/8 signaling and Klf4 protein were increased (p<0.01). Moreover, elevated proteolytic activity of MMP2 and MMP9 was linked to a 50% reduction of lung elastic fibres. In conclusion, we show a possible link of LBW in humans and reduced lung function in adulthood. Experimental IUGR identifies an intrauterine phase with inhibition of angiogenic signaling, and a postnatal phase with proteolytic activity and reduced elastic fibres.

    View details for DOI 10.1038/s41598-020-79245-7

    View details for PubMedID 33372189

  • Inherited Extremes of Aortic Diameter Confer Risk for a Specific Class of Congenital Heart Disease. Circulation. Genomic and precision medicine Tcheandjieu, C., Zanetti, D., Yu, M., Priest, J. R. 2020

    View details for DOI 10.1161/CIRCGEN.120.003170

    View details for PubMedID 33191768

  • Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses. Hypertension (Dallas, Tex. : 1979) Zanetti, D., Bergman, H., Burgess, S., Assimes, T. L., Bhalla, V., Ingelsson, E. 2020: HYPERTENSIONAHA11914028


    Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, heart failure, hemorrhagic stroke, lipid-lowering medication, and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (beta systolic BP ≥2.63; beta diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; P≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, P=0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.

    View details for DOI 10.1161/HYPERTENSIONAHA.119.14028

    View details for PubMedID 32008434

  • Comprehensive Investigation of Circulating Biomarkers and their Causal Role in Atherosclerosis-related Risk Factors and Clinical Events. Circulation. Genomic and precision medicine Zanetti, D. n., Gustafsson, S. n., Assimes, T. L., Ingelsson, E. n. 2020


    Background - Circulating biomarkers have been previously associated with atherosclerosis related risk factors, but the nature of these associations is incompletely understood. Methods - We performed multivariable-adjusted regressions and two-sample Mendelian randomization (MR) analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to 451,933 participants of the UK Biobank. Results - After multiple-testing correction (alpha=1.3*10-4), we found a total of 15, 9, 21, 22, 26, 24 and 26 biomarkers strongly associated with coronary artery disease (CAD), ischemic stroke, atrial fibrillation, type 2 diabetes (T2D), systolic blood pressure (SBP), body mass index (BMI) and waist-to-hip ratio (WHR); respectively. The MR analyses confirmed strong evidence of previously suggested causal associations for several glucose- and lipid-related biomarkers with T2D and CAD. Particularly interesting findings included a protective role of insulin-like growth factor 1 in SBP, and the strong causal association of lipoprotein(a) in CAD development (β, -0.13; per SD change in exposure and outcome and OR, 1.28; P=2.6*10-4 and P=7.4*10-35, respectively). In addition, our results indicated a causal role of increased alanine aminotransferase in the development of T2D and hypertension (OR, 1.59 and β,0.06, per SD change in exposure and outcome; P=4.8*10-11 and P=6.0*10-5). Our results suggest that it is unlikely that C-reactive protein and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease. Conclusions - We confirmed and extended known associations, and reported several novel causal associations providing important insights regarding the etiology of these diseases, which can help accelerate new prevention strategies.

    View details for DOI 10.1161/CIRCGEN.120.002996

    View details for PubMedID 33125266

  • Commonly used clinical chemistry tests as mortality predictors: Results from two large cohort studies. PloS one Lind, L., Zanetti, D., Hogman, M., Sundman, L., Ingelsson, E. 2020; 15 (11): e0241558


    BACKGROUND: The normal ranges for clinical chemistry tests are usually defined by cut-offs given by the distribution in healthy individuals. This approach does however not indicate if individuals outside the normal range are more prone to disease.METHODS: We studied the associations and risk prediction of 11 plasma and serum biomarkers with all-cause mortality in two population-based cohorts: a Swedish cohort (X69) initiated in 1969, and the UK Biobank (UKB) initiated in 2006-2010, with up to 48- and 9-years follow-up, respectively.RESULTS: In X69 and in UKB, 18,529 and 425,264 individuals were investigated, respectively. During the follow-up time, 14,475 deaths occurred in X69 and 17,116 in UKB. All evaluated tests were associated with mortality in X69 (P<0.0001, except bilirubin P<0.005). For calcium, blood urea nitrogen, bilirubin, hematocrit, uric acid, and iron, U-shaped associations were seen (P<0.0001). For leukocyte count, gamma-glutamyl transferase, alkaline phosphatases and lactate dehydrogenase, linear positive associations were seen, while for albumin the association was negative. Similar associations were seen in UKB. Addition of all biomarkers to a model with classical risk factors improved mortality prediction (delta C-statistics: +0.009 in X69 and +0.023 in UKB, P<0.00001 in both cohorts).CONCLUSIONS: Commonly used clinical chemistry tests were associated with all-cause mortality both in the medium- and long-term perspective, and improved mortality prediction beyond classical risk factors. Since both linear and U-shaped relationships were found, we propose to define the normal range of a clinical chemistry test based on its association with mortality, rather than from the distribution.

    View details for DOI 10.1371/journal.pone.0241558

    View details for PubMedID 33152050

  • No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation DIABETOLOGIA Harati, H., Zanetti, D., Rao, A., Gustafsson, S., Perez, M., Ingelsson, E., Knowles, J. W. 2019; 62 (5): 800–804
  • Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion KIDNEY INTERNATIONAL Zanetti, D., Rao, A., Gustafsson, S., Assimes, T. L., Montgomery, S. B., Ingelsson, E. 2019; 95 (5): 1197–1208
  • Clinical and Genetic Determinants of Varicose Veins Prospective, Community-Based Study of approximate to 500 000 Individuals CIRCULATION Fukaya, E., Flores, A. M., Lindholm, D., Gustafsson, S., Zanetti, D., Ingelsson, E., Leeper, N. J. 2018; 138 (25): 2869–80
  • Identification of 22 novel loci associated withurinary biomarkers of albumin, sodium, andpotassium excretion. Kidney international Zanetti, D., Rao, A., Gustafsson, S., Assimes, T. L., Montgomery, S. B., Ingelsson, E. 2019


    Urine biomarkers reflecting kidney function and handling of dietary sodium and potassium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease, and diabetes mellitus. Knowledge about the genetic determinants of these biomarkers may shed light on pathophysiological mechanisms underlying the development of these diseases. We performed genome-wide association studies of urinary albumin: creatinine ratio (UACR), urinary potassium: creatinine ratio (UK/UCr), urinary sodium: creatinine ratio (UNa/UCr) and urinary sodium: potassium ratio (UNa/UK) in up to 218,450 (discovery) and 109,166 (replication) unrelated individuals of European ancestry from the UK Biobank. Further, we explored genetic correlations, tissue-specific gene expression, and possible genes implicated in the regulation of these biomarkers. After replication, we identified 19 genome-wide significant independent loci associated with UACR, 6 each with UK/UCr and UNa/UCr, and 4 with UNa/UK. In addition to 22 novel associations, we confirmed several established associations, including between the CUBN locus and microalbuminuria. We detected high pairwise genetic correlation across the urinary biomarkers, and between their levels and several physiological measurements. We highlight GIPR, a potential diabetes drug target, as possibly implicated in the genetic control of urinary potassium excretion, and NRBP1, a locus associated with gout, as plausibly involved in sodium and albumin excretion. Overall, we identified 22 novel genome-wide significant associations with urinary biomarkers and confirmed several previously established associations, providing new insights into the genetic basis of these traits and their connection to chronic diseases.

    View details for PubMedID 30910378

  • No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation. Diabetologia Harati, H., Zanetti, D., Rao, A., Gustafsson, S., Perez, M., Ingelsson, E., Knowles, J. W. 2019


    AIMS/HYPOTHESIS: Several epidemiological studies have shown an increased risk of atrial fibrillation in individuals with type 2 diabetes or milder forms of dysglycaemia. We aimed to assess whether this relation is causal using a Mendelian randomisation approach.METHODS: Two-sample Mendelian randomisation was used to obtain estimates of the influence of type 2 diabetes, fasting blood glucose (FBG), and HbA1c on the risk of atrial fibrillation. Instrumental variables were constructed using available summary statistics from meta-analyses of genome-wide association studies (GWAS) for type 2 diabetes and associated phenotypes. Pleiotropic SNPs were excluded from the analyses. The most recent GWAS meta-analysis summary statistics for atrial fibrillation, which included over 1 million individuals (approximately 60,000 individuals with atrial fibrillation) was used for outcome analysis.RESULTS: Neither type 2 diabetes (OR 1.01 [95% CI 0.98, 1.03]; p=0.37), nor FBG (OR 0.95 [95% CI 0.82, 1.09] per mmol/l; p=0.49) or HbA1c (OR 1.01 [95% CI, 0.85, 1.17] per mmol/mol [%]; p=0.88) were associated with atrial fibrillation in Mendelian randomisation analyses. We had >80% statistical power to detect ORs of 1.08, 1.06 and 1.09 or larger for type 2 diabetes, FBG and HbA1c, respectively, for associations with atrial fibrillation.CONCLUSIONS/INTERPRETATION: This Mendelian randomisation analysis does not support a causal role of clinical significance between genetically programmed type 2 diabetes, FBG or HbA1c and development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective strategy for atrial fibrillation prevention.DATA AVAILABILITY: The datasets analysed during the current study are available from the following repository: Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al (2018) GWAS summary statistics for AF (N=60,620 AF cases and 970,216 controls). Center for Statistical Genetics:

    View details for PubMedID 30810766

  • Clinical and Genetic Determinants of Varicose Veins. Circulation Fukaya, E., Flores, A. M., Lindholm, D., Gustafsson, S., Zanetti, D., Ingelsson, E., Leeper, N. J. 2018; 138 (25): 2869–80


    BACKGROUND: Varicose veins are a common problem with no approved medical therapies. Although it is believed that varicose vein pathogenesis is multifactorial, there is limited understanding of the genetic and environmental factors that contribute to their formation. Large-scale studies of risk factors for varicose veins may highlight important aspects of pathophysiology and identify groups at increased risk for disease.METHODS: We applied machine learning to agnostically search for risk factors of varicose veins in 493519 individuals in the UK Biobank. Predictors were further studied with univariable and multivariable Cox regression analyses (2441 incident events). A genome-wide association study of varicose veins was also performed among 337536 unrelated individuals (9577 cases) of white British descent, followed by expression quantitative loci and pathway analyses. Because height emerged as a new candidate risk factor, we performed mendelian randomization analyses to assess a potential causal role for height in varicose vein development.RESULTS: Machine learning confirmed several known (age, sex, obesity, pregnancy, history of deep vein thrombosis) and identified several new risk factors for varicose vein disease, including height. After adjustment for traditional risk factors in Cox regression, greater height remained independently associated with varicose veins (hazard ratio for upper versus lower quartile, 1.74; 95% CI, 1.51-2.01; P<0.0001). A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development and skeletal/limb biology. Mendelian randomization analysis provided evidence that increased height is causally related to varicose veins (inverse-variance weighted: odds ratio, 1.26; P=2.07*10-16).CONCLUSIONS: Using data from nearly a half-million individuals, we present a comprehensive genetic and epidemiological study of varicose veins. We identified novel clinical and genetic risk factors that provide pathophysiological insights and could help future improvements of treatment of varicose vein disease.

    View details for PubMedID 30566020

  • Transethnic differences in GWAS signals: A simulation study. Annals of human genetics Zanetti, D., Weale, M. E. 2018


    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. To determine whether properties (1)-(3) on their own might be sufficient to explain the patterns previously noted in strong GWAS signals, we simulated case-control data of European, Asian and African ancestry, applying realistic allele frequencies and LD from 1000 Genomes data but enforcing equal causal effect sizes across populations. Much of the observed differences in strong GWAS signals could indeed be accounted for by allele frequency and LD differences, enhanced by the Euro-centric SNP bias and lower SNP coverage found in older GWAS panels. While we cannot rule out a role for true transethnic effect size differences, our results suggest that strong causal effects may be largely shared among human populations, motivating the use of transethnic data for fine-mapping.

    View details for PubMedID 29733446

  • Birthweight, Type 2 Diabetes Mellitus, and Cardiovascular Disease: Addressing the Barker Hypothesis With Mendelian Randomization. Circulation. Genomic and precision medicine Zanetti, D. n., Tikkanen, E. n., Gustafsson, S. n., Priest, J. R., Burgess, S. n., Ingelsson, E. n. 2018; 11 (6): e002054


    Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies.We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237 631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization.In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (β, -0.83 and -0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], -0.90 to -0.75 and -0.31 to -0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79-0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81-0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78-0.94), whereas the associations with adult body mass index and body fat (β, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03-0.04 and 0.01-0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure.Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension.

    View details for PubMedID 29875125

  • Analysis of Genomic Regions Associated With Coronary Artery Disease Reveals Continent-Specific Single Nucleotide Polymorphisms in North African Populations JOURNAL OF EPIDEMIOLOGY Zanetti, D., Via, M., Carreras-Torres, R., Esteban, E., Chaabani, H., Anaibar, F., Harich, N., Habbal, R., Ghalim, N., Moral, P. 2016; 26 (5): 264-271


    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.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.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.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.

    View details for DOI 10.2188/jea.JE20150034

    View details for Web of Science ID 000375919300005

    View details for PubMedID 26780859

  • Potential Signals of Natural Selection in the Top Risk Loci for Coronary Artery Disease: 9p21 and 10q11 PLOS ONE Zanetti, D., Carreras-Torres, R., Esteban, E., Via, M., Moral, P. 2015; 10 (8)


    Coronary artery disease (CAD) is a complex disease and the leading cause of death in the world. Populations of different ancestry do not always share the same risk markers. Natural selective processes may be the cause of some of the population differences detected for specific risk mutations.In this study, 384 single nucleotide polymorphisms (SNPs) located in four genomic regions associated with CAD (1p13, 1q41, 9p21 and 10q11) are analysed in a set of 19 populations from Europe, Middle East and North Africa and also in Asian and African samples from the 1000 Genomes Project. The aim of this survey is to explore for the first time whether the genetic variability in these genomic regions is better explained by demography or by natural selection.The results indicate significant differences in the structure of genetic variation and in the LD patterns among populations that probably explain the population disparities found in markers of susceptibility to CAD.The results are consistent with potential signature of positive selection in the 9p21 region and of balancing selection in the 9p21 and 10q11. Specifically, in Europe three CAD risk markers in the 9p21 region (rs9632884, rs1537371 and rs1333042) show consistent signals of positive selection. The results of this study are consistent with a potential selective role of CAD in the configuration of genetic diversity in current human populations.

    View details for DOI 10.1371/journal.pone.0134840

    View details for Web of Science ID 000359121100080

    View details for PubMedID 26252781

  • Human Diversity in Jordan: Polymorphic Alu Insertions in General Jordanian and Bedouin Groups HUMAN BIOLOGY Zanetti, D., Sadiq, M., Carreras-Torres, R., Khabour, O., Alkaraki, A., Esteban, E., Via, M., Moral, P. 2014; 86 (2): 131-138


    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 diffferences 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.

    View details for DOI 10.3378/027.086.0201

    View details for Web of Science ID 000346343500005

    View details for PubMedID 25397703