Publications by authors named "Erika Salvi"

65 Publications

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Computational pipeline to probe NaV1.7 gain-of-function variants in neuropathic painful syndromes.

Sci Rep 2020 10 21;10(1):17930. Epub 2020 Oct 21.

Dipartimento di Scienze Ambientali, Informatica e Statistica, Universitá Ca' Foscari Venezia, Venezia-Mestre, Italy.

Applications of machine learning and graph theory techniques to neuroscience have witnessed an increased interest in the last decade due to the large data availability and unprecedented technology developments. Their employment to investigate the effect of mutational changes in genes encoding for proteins modulating the membrane of excitable cells, whose biological correlates are assessed at electrophysiological level, could provide useful predictive clues. We apply this concept to the analysis of variants in sodium channel NaV1.7 subunit found in patients with chronic painful syndromes, by the implementation of a dedicated computational pipeline empowering different and complementary techniques including homology modeling, network theory, and machine learning. By testing three templates of different origin and sequence identities, we provide an optimal condition for its use. Our findings reveal the usefulness of our computational pipeline in supporting the selection of candidates for cell electrophysiology assay and with potential clinical applications.
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http://dx.doi.org/10.1038/s41598-020-74591-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578092PMC
October 2020

Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy.

J Am Soc Nephrol 2020 12 10;31(12):2949-2963. Epub 2020 Sep 10.

Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Background: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk.

Methods: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny.

Results: Identification of three novel loci (rs6427389 on 1q23.1 [=8.18×10, OR=1.132], rs6942325 on 6p25.3 [=1.62×10, OR=1.165], and rs2240335 on 1p36.13 [=5.10×10, OR=1.114]), implicates , , and as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of , and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on . Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119).

Conclusions: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations.
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http://dx.doi.org/10.1681/ASN.2019080799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790208PMC
December 2020

Evaluation of molecular inversion probe versus TruSeq® custom methods for targeted next-generation sequencing.

PLoS One 2020 2;15(9):e0238467. Epub 2020 Sep 2.

Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, the Netherlands.

Resolving the genetic architecture of painful neuropathy will lead to better disease management strategies. We aimed to develop a reliable method to re-sequence multiple genes in a large cohort of painful neuropathy patients at low cost. In this study, we compared sensitivity, specificity, targeting efficiency, performance and cost effectiveness of Molecular Inversion Probes-Next generation sequencing (MIPs-NGS) and TruSeq® Custom Amplicon-Next generation sequencing (TSCA-NGS). Capture probes were designed to target nine sodium channel genes (SCN3A, SCN8A-SCN11A, and SCN1B-SCN4B). One hundred sixty-six patients with diabetic and idiopathic neuropathy were tested by both methods, 70 patients were validated by Sanger sequencing. Sensitivity, specificity and performance of both techniques were comparable, and in agreement with Sanger sequencing. The average targeted regions coverage for MIPs-NGS was 97.3% versus 93.9% for TSCA-NGS. MIPs-NGS has a more versatile assay design and is more flexible than TSCA-NGS. The cost of MIPs-NGS is >5 times cheaper than TSCA-NGS when 500 or more samples are tested. In conclusion, MIPs-NGS is a reliable, flexible, and relatively inexpensive method to detect genetic variations in a large cohort of patients. In our centers, MIPs-NGS is currently implemented as a routine diagnostic tool for screening of sodium channel genes in painful neuropathy patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238467PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467307PMC
October 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

Diagnostic criteria for small fibre neuropathy in clinical practice and research.

Brain 2019 12;142(12):3728-3736

Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.

The diagnostic criteria for small fibre neuropathy are not established, influencing the approach to patients in clinical practice, their access to disease-modifying and symptomatic treatments, the use of healthcare resources, and the design of clinical trials. To address these issues, we performed a reappraisal study of 150 patients with sensory neuropathy and a prospective and follow-up validation study of 352 new subjects with suspected sensory neuropathy. Small fibre neuropathy diagnostic criteria were based on deep clinical phenotyping, quantitative sensory testing (QST) and intraepidermal nerve fibre density (IENFD). Small fibre neuropathy was ruled out in 5 of 150 patients (3.3%) of the reappraisal study. Small fibre neuropathy was diagnosed at baseline of the validation study in 149 of 352 patients (42.4%) based on the combination between two clinical signs and abnormal QST and IENFD (69.1%), abnormal QST alone (5.4%), or abnormal IENFD alone (20.1%). Eight patients (5.4%) had abnormal QST and IENFD but no clinical signs. Further, 38 patients complained of sensory symptoms but showed no clinical signs. Of those, 34 (89.4%) had normal QST and IENFD, 4 (10.5%) had abnormal QST and normal IENFD, and none had abnormal IENFD alone. At 18-month follow-up, 19 of them (56%) reported the complete recovery of symptoms and showed normal clinical, QST and IENFD findings. None of those with one single abnormal test (QST or IENFD) developed clinical signs or showed abnormal findings on the other test. Conversely, all eight patients with abnormal QST and IENFD at baseline developed clinical signs at follow-up. The combination of clinical signs and abnormal QST and/or IENFD findings can more reliably lead to the diagnosis of small fibre neuropathy than the combination of abnormal QST and IENFD findings in the absence of clinical signs. Sensory symptoms alone should not be considered a reliable screening feature. Our findings demonstrate that the combined clinical, functional and structural approach to the diagnosis of small fibre neuropathy is reliable and relevant both for clinical practice and clinical trial design.
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http://dx.doi.org/10.1093/brain/awz333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906595PMC
December 2019

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
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http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019

Genome-Wide Meta-Analysis of Blood Pressure Response to β-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies).

J Am Heart Assoc 2019 08 19;8(16):e013115. Epub 2019 Aug 19.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine University of Florida Gainesville FL.

BackgroundThere exists a wide interindividual variability in blood pressure (BP) response to β-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants influencing β-blocker BP response.Methods and ResultsGenome-wide association analysis for systolic BP and diastolic BP response to β-blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta-analysis and single nucleotide polymorphisms (SNPs) with P<10 were tested for replication in 2 independent randomized clinical trials of β-blocker-treated patients of European ancestry (n=1552). Regions harboring the replicated SNPs were validated in a β-blocker-treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST1 was associated with systolic BP response to β-blockers in the discovery meta-analysis (P=9.33×10, β=-3.21 mm Hg) and replicated at Bonferroni significance (P=1.85×10, β=-4.86 mm Hg) in the replication meta-analysis with combined meta-analysis approaching genome-wide significance (P=2.18×10). This SNP in BST1 is in linkage disequilibrium with several SNPs with putative regulatory functions in nearby genes, including CD38, FBXL5, and FGFBP1, all of which have been implicated in BP regulation. SNPs in this genetic region were also associated with BP response in the black cohort.ConclusionsData from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST1 containing locus on chromosome 4 is associated with β-blocker BP response. Given the previous associations of this region with BP, this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.
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http://dx.doi.org/10.1161/JAHA.119.013115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759913PMC
August 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

A red orange and lemon by-products extract rich in anthocyanins inhibits the progression of diabetic nephropathy.

J Cell Physiol 2019 12 29;234(12):23268-23278. Epub 2019 May 29.

Department of Veterinary Medicine and Animal Productions, University of Naples "Federico II", Napoli, Italy.

The major cause of end-stage renal disease is the diabetic nephropathy. Oxidative stress contributes to the development of type II diabetes mellitus (T2DM). In this study we have evaluated the effect of a diet with a new standardized of red orange and lemon extract (RLE) rich in anthocyanins (ANT) in the progression of the kidney disease on Zucker diabetic fatty rats. Oxidative stress and renal function were analyzed. In diabetic rats, the RLE restored the blood glucose levels, body weight, and normalized the reactive oxygen species (ROS) total pathways. The kidney inflammation, in diabetic rats, has not shown significant change, showing that the oxidative stress rather than to inflammatory processes is a triggering factor in the renal complication associated with T2DM. Therefore, the administration of the RLE prevents this complication and this effect could be related to the inhibition of ROS production.
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http://dx.doi.org/10.1002/jcp.28893DOI Listing
December 2019

Claudin-14 Gene Polymorphisms and Urine Calcium Excretion.

Clin J Am Soc Nephrol 2018 10 19;13(10):1542-1549. Epub 2018 Sep 19.

Nephrology and Dialysis Unit, IRCCS San Raffaele Scientific Institute, Genomics of Renal Diseases and Hypertension Unit, Vita Salute San Raffaele University, Milan, Italy;

Background And Objectives: Claudin-16 and -19 are proteins forming pores for the paracellular reabsorption of divalent cations in the ascending limb of Henle loop; conversely, claudin-14 decreases ion permeability of these pores. Single-nucleotide polymorphisms in gene coding for were associated with kidney stones and calcium excretion. This study aimed to explore the association of , , and single-nucleotide polymorphisms with calcium excretion.

Design, Setting, Participants, & Measurements: We performed a retrospective observational study of 393 patients with hypertension who were naïve to antihypertensive drugs, in whom we measured 24-hour urine calcium excretion; history of kidney stones was ascertained by interview; 370 of these patients underwent an intravenous 0.9% sodium chloride infusion (2 L in 2 hours) to evaluate the response of calcium excretion in three different 2-hour urine samples collected before, during, and after saline infusion. Genotypes of , , and were obtained from data of a previous genome-wide association study in the same patients.

Results: Thirty-one single-nucleotide polymorphisms of the 3' region of the gene were significantly associated with 24-hour calcium excretion and calcium excretion after saline infusion. The most significant associated single-nucleotide polymorphism was rs219755 (24-hour calcium excretion in GG, 225±124 mg/24 hours; 24-hour calcium excretion in GA, 194±100 mg/24 hours; 24-hour calcium excretion in AA, 124±73 mg/24 hours; <0.001; calcium excretion during saline infusion in GG, 30±21 mg/2 hours; calcium excretion during saline infusion in GA, 29±18 mg/2 hours; calcium excretion during saline infusion in AA, 17±11 mg/2 hours; =0.03). No significant associations were found among and single-nucleotide polymorphisms and calcium excretion and between , , and single-nucleotide polymorphisms and stones. Bioinformatic analysis showed that one single-nucleotide polymorphism at among those associated with calcium excretion may potentially influence splicing of transcript.

Conclusions: genotype at the 3' region is associated with calcium excretion in 24-hour urine and after the calciuretic stimulus of saline infusion.
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http://dx.doi.org/10.2215/CJN.01770218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218816PMC
October 2018

A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia.

J Peripher Nerv Syst 2018 09 23;23(3):202-206. Epub 2018 Jul 23.

Neuroalgology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy.

Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder presenting with a spectrum of clinical features caused by mutations in different genes. A 10-year-old girl with CIP, hyposmia and hypogeusia, and her unaffected twin and parents underwent next generation sequencing of SCN9A exons and flanking splice sites. Transcript analysis from whole blood successfully assayed the effect of the mutation on the mRNA splicing by polymerase chain reaction amplification on cDNA and Sanger sequencing. We identified the novel splicing variant c.1108-2A>G compound with the p.Arg896Gln (c.2687G>A) missense mutation previously described in a homozygous patient. The new intronic variant was predicted to induce exon 10 skipping. Conversely, SCN9A mRNA assay demonstrated its partial deletion with a loss of 46 nucleotides causing a premature stop codon in position p.Gln369 (NP_002968). Genetic analysis showed that the two variants were biallelic, being the mother and brother heterozygous carriers of the missense mutation, and the father heterozygous for the splicing mutation. Skin biopsy showed lack of Meissner's corpuscles, loss of epidermal nociceptors and normal autonomic organ innervation. We report a novel splicing mutation and provide clues on its pathogenic effect, broadening the spectrum of genotypes and phenotypes associated to CIP.
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http://dx.doi.org/10.1111/jns.12280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767138PMC
September 2018

A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia.

PLoS One 2017 11;12(10):e0185797. Epub 2017 Oct 11.

Department of Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy.

Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer's disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636111PMC
October 2017

CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.

Nat Commun 2017 09 29;8(1):744. Epub 2017 Sep 29.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m for each Mb of total deletion burden (P = 2.5 × 10, 6.0 × 10, and 2.9 × 10). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.
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http://dx.doi.org/10.1038/s41467-017-00556-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622064PMC
September 2017

Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

Nat Commun 2017 06 14;8:15805. Epub 2017 Jun 14.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74
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http://dx.doi.org/10.1038/ncomms15805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474732PMC
June 2017

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Nat Genet 2017 07 29;49(7):993-1004. Epub 2017 May 29.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
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http://dx.doi.org/10.1038/ng.3875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685441PMC
July 2017

Next-generation sequencing of a family with a high penetrance of monoclonal gammopathies for the identification of candidate risk alleles.

Cancer 2017 Oct 23;123(19):3701-3708. Epub 2017 May 23.

Department of Hematology and Pediatric Onco-Hematology, IRCCS Foundation National Cancer Institute, Milan, Italy.

Background: The authors describe a family with a high penetrance of plasma cell dyscrasias, suggesting inheritance of an autosomal dominant risk allele.

Methods: The authors performed whole-exome sequencing and reported on a combined approach aimed at the identification of causative variants and risk loci, using the wealth of data provided by this approach.

Results: The authors identified gene mutations and single-nucleotide polymorphisms of potential significance, and pinpointed a known risk locus for myeloma as a potential area of transmissible risk in the family.

Conclusions: To the authors' knowledge, the current study is the first to provide a whole-exome sequencing approach to such cases, and a framework analysis that could be applied to further understanding of the inherited risk of developing plasma cell dyscrasias. Cancer 2017;123:3701-3708. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30777DOI Listing
October 2017

Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1.

Nat Commun 2017 05 23;8:15466. Epub 2017 May 23.

Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.

Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXRα (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression.
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http://dx.doi.org/10.1038/ncomms15466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457519PMC
May 2017

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population.

BMC Med Genet 2017 04 27;18(1):45. Epub 2017 Apr 27.

Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences,, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 35, Box 7001, BE-3000, Leuven, Belgium.

Background: Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population.

Methods: In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus.

Results: Over a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056).

Conclusions: In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.
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http://dx.doi.org/10.1186/s12881-017-0411-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408434PMC
April 2017

The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population.

Nephrol Dial Transplant 2018 03;33(3):514-522

Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.

Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP).

Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables.

Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results.

Conclusion: Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established.
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http://dx.doi.org/10.1093/ndt/gfx014DOI Listing
March 2018

and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

J Am Soc Nephrol 2017 Mar 5;28(3):981-994. Epub 2016 Dec 5.

Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
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http://dx.doi.org/10.1681/ASN.2016020131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328154PMC
March 2017

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.

Nat Commun 2016 11 23;7:13357. Epub 2016 Nov 23.

Department of Kinesiology, Laval University, Québec, Québec, Canada G1V 0A6.

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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http://dx.doi.org/10.1038/ncomms13357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114527PMC
November 2016

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide.

Hypertension 2017 01 31;69(1):51-59. Epub 2016 Oct 31.

From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).

This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10), and the suggestive regions (P<10) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10 ). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.08267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5145728PMC
January 2017

Association Analysis of Noncoding Variants in Neuroligins 3 and 4X Genes with Autism Spectrum Disorder in an Italian Cohort.

Int J Mol Sci 2016 Oct 22;17(10). Epub 2016 Oct 22.

Institute of Biomedical Technologies, National Research Council, Via Fratelli Cervi 93, 20090 Segrate, Italy.

Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants in and genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP) array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multiple loci approach. According to both the European and the Italian control groups, a 6-marker haplotype on (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58, -value = 2.58 × 10 for the European controls; odds ratio = 2.42, -value = 6.33 × 10 for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms on may be associated to autism, suggesting the key role of in autism pathophysiology and in its male prevalence.
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http://dx.doi.org/10.3390/ijms17101765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085789PMC
October 2016

A candidate gene study identifies a haplotype of CD2 as novel susceptibility factor for systemic sclerosis.

Clin Exp Rheumatol 2016 Sep-Oct;34 Suppl 100(5):43-48. Epub 2016 Jul 1.

INSERM, Institut Cochin, INSERM U1016, Sorbonne Paris Cité, and Paris Descartes University, Paris; and Paris Descartes University, Rheumatology A Department, Cochin Hospital, APHP, Paris, France.

Objectives: Systemic sclerosis (SSc) is a rare autoimmune disease (AID) with a complex genetic etiology. Evidence for a shared pathogenesis across AIDs is given by the well-known pleiotropism of autoimmune genes. Recently, several unbiased approaches have identified an association between polymorphisms of the CD2 gene, and rheumatoid arthritis (RA) susceptibility. The objective of this study was to investigate whether CD2 polymorphisms are associated with SSc.

Methods: Two SNPs of CD2, rs624988 and rs798036, were genotyped in a total of 1,786 SSc patients and 2,360 healthy individuals from two European populations (France and Italy). Meta-analyses were performed to assess whether an association exists between CD2 polymorphisms or haplotypes and SSc or its main subtypes.

Results: The combined analyses revealed an association between the rs624988 A allele and SSc susceptibility: padj=0.023, OR=1.14 (95%CI 1.04-1.25). Single marker analysis did not reveal any association between rs798036 and SSc. Haplotype analysis identified that the A-T haplotype, previously described in RA, was associated with higher susceptibility for SSc (padj=0.029, OR=1.14, 95%CI 1.04-1.25) and with the positive anti-centromere antibody sub-group of SSc patients (padj=0.009, OR=1.19 95%CI 1.07-1.32). Genotype-mRNA expression correlations revealed that the CD2 risk haplotype was associated with decreased CD2 mRNA expression in SSc patients.

Conclusions: Our study establishes CD2 as a new susceptibility factor for SSc, in a European Caucasian population, confirming the sharing of autoimmune risk factors by SSc and RA.
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January 2017

Xanthine oxidase gene variants and their association with blood pressure and incident hypertension: a population study.

J Hypertens 2016 11;34(11):2147-54

aDivision of Rheumatology, Department of Internal Medicine, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre+, Maastricht, The Netherlands bStudies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium cFirst Department of Cardiology and Hypertension, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College, Kraków, Poland dInstitute of Internal and Preventive Medicine, Novosibirsk, Russian Federation eDepartment of Clinical and Experimental Medicine, University of Padova, Padova fDepartment of Health Sciences, University of Milan, Milan, Italy gFaculty of Medicine, Charles University, Pilsen, Czech Republic hSchool of Nephrology, Vita-Salute San Raffaele University iInstitute of Biomedical Technologies, Italian National Centre of Research, Milan, Italy jVitaK R & D Group kDepartment of Epidemiology, CAPHRI School for Public Health and Primary Care, CARIM School for Cardiovascular Sciences, and MaCSBio Maastricht Centre for Systems Biology, Maastricht University, Maastricht, The Netherlands.

Objective: The enzyme xanthine oxidoreductase (XOR) generates uric acid in the terminal steps of the purine metabolism; meanwhile reactive oxygen species are formed. We hypothesized that uric acid production, as assessed indirectly from XOR variants, is associated with hypertension.

Methods: Among 2769 participants (48.3% men; mean age 40.7 years) randomly recruited from European populations, we genotyped 25 tagging XOR SNPs and measured blood pressure (BP) at baseline and follow-up (median 8.8 years). The relation between variants of the XOR gene with changes in pulse pressure and mean arterial pressure over time; and incidence of hypertension, were analyzed.

Results: Compared with nonminor allele carriers, pulse pressure increased approximately 2 mmHg more in minor allele carriers of rs11904439 (P = 0.01), whereas mean arterial pressure and DBP increased approximately 1 mmHg less in minor allele carriers of rs2043013 (P = 0.01). In 2050, participants normotensive at baseline, hazard ratios contrasting risk of hypertension in minor allele carriers vs. nonminor allele carriers were 1.31 (95% confidence interval 1.03-1.68; P = 0.02) and 1.69 (95% confidence interval 1.11-2.57; P = 0.01) for rs11904439 and rs148756340, respectively. With the false discovery rate set at 0.25, the aforementioned associations retained significance. The changes in SBP from baseline to follow-up and the serum levels of uric acid at baseline (n = 1949) were not associated with XOR.

Conclusion: Pending confirmation, our findings suggest that variation in uric acid production, as captured by genetic variation in XOR, might be a predictor of changes in BP and in the risk of hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000001077DOI Listing
November 2016

Interaction between polyphenols intake and PON1 gene variants on markers of cardiovascular disease: a nutrigenetic observational study.

J Transl Med 2016 06 23;14(1):186. Epub 2016 Jun 23.

Genomics and Bionformatics Unit, Department of Health Sciences, Università degli Studi di Milano, viale Ortles 22/4, Milan, Italy.

Background: Paraoxonase 1 (PON1) gene polymorphisms and polyphenols intake have been reported independently associated to lipid profile and susceptibility to atherosclerosis and cardiovascular disease. However, the interaction between these factors remains to be investigated. We performed an observational nutrigenetic study to examine whether the interaction between polyphenols and anthocyanins intake and PON1 genetic variants can modulate biomarkers of cardiovascular health in an Italian healthy population.

Methods: We recruited 443 healthy volunteers who participated in the EC funded ATHENA project (AnThocyanin and polyphenols bioactive for Health Enhancement through Nutritional Advancement). Data collection included detailed demographic, clinical, dietary, lifestyle, biochemical and genetic data. Polyphenols and anthocyanins intake was measured by 24 h dietary recall repeated three times a year in order to get seasonal variations. We tested the interaction between 18 independent tagging SNPs in PON1 gene and polyphenols intake on HDL, LDL, cholesterol, triglycerides and atherogenic index of plasma.

Results: Without considering the genetic background, we could not observe significant differences in the lipid profile between high and low polyphenols and anthocyanins intake. Using a nutrigenetic approach, we identified protective genotypes in four independent polymorphisms that, at Bonferroni level (p ≤ 0.0028), present a significant association with increased HDL level under high polyphenols and anthocyanins intake, compared to risk genotypes (rs854549, Beta = 4.7 per C allele; rs854552, Beta = 5.6 per C allele; rs854571, Beta = 3.92 per T allele; rs854572, Beta = 3.94 per C allele).

Conclusions: We highlight the protective role of genetic variants in PON1 towards cardiovascular risk under high polyphenols and anthocyanins consumption. PON1 variants could represent novel biomarkers to stratify individuals who might benefit from targeted dietary recommendation for health promotion and strategies of preventive medicine.
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http://dx.doi.org/10.1186/s12967-016-0941-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918189PMC
June 2016

Genome-wide association study identifies 74 loci associated with educational attainment.

Nature 2016 05 11;533(7604):539-42. Epub 2016 May 11.

Department of Neurology, General Hospital and Medical University Graz, Graz 8036, Austria.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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http://dx.doi.org/10.1038/nature17671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883595PMC
May 2016
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