Publications by authors named "Nicola Pirastu"

54 Publications

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

Genetic analyses identify widespread sex-differential participation bias.

Nat Genet 2021 05 22;53(5):663-671. Epub 2021 Apr 22.

Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00846-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611642PMC
May 2021

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.04.01.21254789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043484PMC
April 2021

The best COVID-19 predictor is recent smell loss: a cross-sectional study.

medRxiv 2020 Jul 28. Epub 2020 Jul 28.

Background: COVID-19 has heterogeneous manifestations, though one of the most common symptoms is a sudden loss of smell (anosmia or hyposmia). We investigated whether olfactory loss is a reliable predictor of COVID-19.

Methods: This preregistered, cross-sectional study used a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified singular and cumulative predictors of COVID-19 status and post-COVID-19 olfactory recovery.

Results: Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both single and cumulative feature models (ROC AUC=0.72), with additional features providing no significant model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms, such as fever or cough. Olfactory recovery within 40 days was reported for ~50% of participants and was best predicted by time since illness onset.

Conclusions: As smell loss is the best predictor of COVID-19, we developed the ODoR-19 tool, a 0-10 scale to screen for recent olfactory loss. Numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (10
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.07.22.20157263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386529PMC
July 2020

More Than Smell-COVID-19 Is Associated With Severe Impairment of Smell, Taste, and Chemesthesis.

Chem Senses 2020 10;45(7):609-622

Department of Anatomy, Faculty of Medicine, Mersin University, Çiftlikköy Campus, Yenişehir, Mersin, Turkey.

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (-79.7 ± 28.7, mean ± standard deviation), taste (-69.0 ± 32.6), and chemesthetic (-37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/chemse/bjaa041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337664PMC
October 2020

Coffee Consumption and Kidney Function: A Mendelian Randomization Study.

Am J Kidney Dis 2020 05 11;75(5):753-761. Epub 2019 Dec 11.

Primary Care & Population Sciences Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Rationale & Objective: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality worldwide, with limited strategies for prevention and treatment. Coffee is a complex mixture of chemicals, and consumption has been associated with mostly beneficial health outcomes. This work aimed to determine the impact of coffee consumption on kidney function.

Study Design: Genome-wide association study (GWAS) and Mendelian randomization.

Setting & Participants: UK Biobank baseline data were used for a coffee consumption GWAS and included 227,666 participants. CKDGen Consortium data were used for kidney outcomes and included 133,814 participants (12,385 cases of CKD) of mostly European ancestry across various countries.

Exposure: Coffee consumption.

Outcomes: Estimated glomerular filtration rate (eGFR), CKD GFR categories 3 to 5 (G3-G5; eGFR<60mL/min/1.73m), and albuminuria.

Analytical Approach: GWAS to identify single-nucleotide polymorphisms (SNPs) associated with coffee consumption in UK Biobank and use of those SNPs in Mendelian randomization analyses of coffee consumption and kidney outcomes in CKDGen.

Results: 2,126 SNPs were associated with coffee consumption (P<5×10), 25 of which were independent and available in CKDGen. Drinking an extra cup of coffee per day conferred a protective effect against CKD G3-G5 (OR, 0.84; 95% CI, 0.72-0.98; P=0.03) and albuminuria (OR, 0.81; 95% CI, 0.67-0.97; P=0.02). An extra cup was also associated with higher eGFR (β=0.022; P=1.6×10) after removal of 3 SNPs responsible for significant heterogeneity (Cochran Q P = 3.5×10).

Limitations: Assays used to measure creatinine and albumin varied between studies that contributed data and a sex-specific definition was used for albuminuria rather than KDIGO guideline recommendations.

Conclusions: This study provides evidence of a beneficial effect of coffee on kidney function. Given widespread coffee consumption and limited interventions to prevent CKD incidence and progression, this could have significant implications for global public health in view of the increasing burden of CKD worldwide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2019.08.025DOI Listing
May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

A genome-wide association study identifies an association between variants in EFCAB4B gene and periodontal disease in an Italian isolated population.

J Periodontal Res 2018 Dec 4;53(6):992-998. Epub 2018 Oct 4.

Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.

Background And Objective: Periodontitis in one of the most prevalent dental diseases. Despite numerous studies have investigated its aetiopathogenetic factors, few works have focused on its genetic predisposition and most of them took into account only candidate genes. Therefore, we conducted a Genome Wide Association Study in an Italian isolated population aimed at uncovering genetic variants that predispose to this disorder.

Methods: Diagnosis of chronic periodontitis was made following the criteria of the American Academy of Periodontology. Patients with chronic periodontitis were grouped into different categories: slight, severe, localized and generalized. A control group composed by people without signs of periodontitis or gingivitis was defined. DNA was genotyped using 370k Illumina chips. Linear mixed model regression was used to test the association between each single nucleotide polymorphism (SNP) (independent variable) and the periodontitis status (dependent variable), controlling for confounders sex, age and smoking. The genomic kinship matrix was also used as random effect.

Results: Four SNPs on the gene EFCAB4B resulted significantly associated to localized periodontitis (P < 5 × 10 ), with the best hit on the rs242016 SNP (P = 1.5 × 10 ).

Conclusion: We have identified a novel significant association between the EFCAB4B gene and localized periodontitis. These results open a new perspective in the understanding of genetic factors contributing to this common disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jre.12598DOI Listing
December 2018

Author Correction: GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk.

Nat Commun 2018 06 29;9(1):2536. Epub 2018 Jun 29.

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.

We have been alerted that in our recent Article the calculations used to transform the heritability from the observed scale to the liability scale did not take into account the individuals in category 2 of the baldness scale, who were removed in our original analysis. This led to an overestimation of the heritability on the liability scale, which should have been 0.62 instead of 0.94. Moreover, in the Title and in the Abstract, we report that we can explain 38% of the risk, while in fact that is the proportion of heritability explained by the loci we discovered. These errors do not substantially change the paper or its conclusions apart from the statement MBP is therefore probably one of the most heritable complex traits. Genome-wide significant associations and pathway analyses are not affected in any way and male-pattern baldness remains less genetically complex than other complex traits. We wish to thank Yap et al. for bringing this to our attention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-04857-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026128PMC
June 2018

Reply to 'Misestimation of heritability and prediction accuracy of male-pattern baldness'.

Nat Commun 2018 06 29;9(1):2538. Epub 2018 Jun 29.

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-04808-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026187PMC
June 2018

GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk.

Nat Commun 2017 11 17;8(1):1584. Epub 2017 Nov 17.

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.

Male pattern baldness (MPB) or androgenetic alopecia is one of the most common conditions affecting men, reaching a prevalence of ~50% by the age of 50; however, the known genes explain little of the heritability. Here, we present the results of a genome-wide association study including more than 70,000 men, identifying 71 independently replicated loci, of which 30 are novel. These loci explain 38% of the risk, suggesting that MPB is less genetically complex than other complex traits. We show that many of these loci contain genes that are relevant to the pathology and highlight pathways and functions underlying baldness. Finally, despite only showing genome-wide genetic correlation with height, pathway-specific genetic correlations are significant for traits including lifespan and cancer. Our study not only greatly increases the number of MPB loci, illuminating the genetic architecture, but also provides a new approach to disentangling the shared biological pathways underlying complex diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-01490-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691155PMC
November 2017

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Nat Commun 2017 10 13;8(1):910. Epub 2017 Oct 13.

Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, Greater, Manchester, M13 9PL, UK.

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-00934-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715013PMC
October 2017

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.

Proc Natl Acad Sci U S A 2016 12 28;113(50):14372-14377. Epub 2016 Nov 28.

Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1611243113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167198PMC
December 2016

Caries and Innate Immunity: DEFB1 Gene Polymorphisms and Caries Susceptibility in Genetic Isolates from North-Eastern Italy.

Caries Res 2016 16;50(6):589-594. Epub 2016 Nov 16.

Department of Medical Sciences, University of Trieste, Trieste, Italy.

Background: The DEFB1 gene, encoding for the constitutively expressed human β-defensin 1 (hBD1) antimicrobial peptide is a potential candidate when studying genetic susceptibility to caries. DEFB1 genetic variations have been reported as contributing to hBD1 production impairment, leading to a greater susceptibility to be infected by oral pathogens, also leading to periodontitis.

Methods: We analysed 5 DEFB1 polymorphisms, namely 3 functional single-nucleotide polymorphisms (SNPs) at the 5'-untranslated region (UTR), -52G>A (rs1799946), -44C>G (rs1800972), and -20G>A (rs11362), 2 SNPs at the 3'-UTR, c*5G>A (rs1047031) and c*87A>G (rs1800971) SNP located in potential miRNA binding sites, looking for possible correlations with the risk to develop caries in 654 adult subjects from isolated populations of north-eastern Italy. Dental caries prevalence was evaluated with the DMFT (decayed, missing, filled teeth) index, calculated after an accurate oral examination. DEFB1 SNP genotyping was performed with an Illumina 370k high-density SNP array.

Results: Two DEFB1 SNPs were significantly associated with the DMFT index: the strongest association emerged from rs11362 SNP (p = 0.008). In particular G/G homozygous individuals showed a higher DMFT index compared to both G/A heterozygous and A/A homozygous individuals; rs1799946 SNP was also significantly associated with DMFT (p = 0.030), and individuals homozygous for the T allele had a higher DMFT value compared to heterozygous C/T and homozygous C/C individuals.

Conclusions: Our study replicated, on a larger number of individuals, previous findings showing the association between two 5'-UTR SNPs in the DEFB1 gene and DMFT, suggesting that these polymorphisms could be considered as potential markers for assessing the risk to develop caries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000450965DOI Listing
December 2017

Non-additive genome-wide association scan reveals a new gene associated with habitual coffee consumption.

Sci Rep 2016 08 25;6:31590. Epub 2016 Aug 25.

Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste Italy.

Coffee is one of the most consumed beverages world-wide and one of the primary sources of caffeine intake. Given its important health and economic impact, the underlying genetics of its consumption has been widely studied. Despite these efforts, much has still to be uncovered. In particular, the use of non-additive genetic models may uncover new information about the genetic variants driving coffee consumption. We have conducted a genome-wide association study in two Italian populations using additive, recessive and dominant models for analysis. This has uncovered a significant association in the PDSS2 gene under the recessive model that has been replicated in an independent cohort from the Netherlands (ERF). The identified gene has been shown to negatively regulate the expression of the caffeine metabolism genes and can thus be linked to coffee consumption. Further bioinformatics analysis of eQTL and histone marks from Roadmap data has evidenced a possible role of the identified SNPs in regulating PDSS2 gene expression through enhancers present in its intron. Our results highlight a novel gene which regulates coffee consumption by regulating the expression of the genes linked to caffeine metabolism. Further studies will be needed to clarify the biological mechanism which links PDSS2 and coffee consumption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep31590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997959PMC
August 2016

A reference panel of 64,976 haplotypes for genotype imputation.

Nat Genet 2016 10 22;48(10):1279-83. Epub 2016 Aug 22.

IRGB, CNR, Sardinia, Italy.

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388176PMC
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature17671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883595PMC
May 2016

A Genome-Wide Association Study in isolated populations reveals new genes associated to common food likings.

Rev Endocr Metab Disord 2016 06;17(2):209-19

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.

Food preferences are the first factor driving food choice and thus nutrition. They involve numerous different senses such as taste and olfaction as well as various other factors such as personal experiences and hedonistic aspects. Although it is clear that several of these have a genetic basis, up to now studies have focused mostly on the effects of polymorphisms of taste receptor genes. Therefore, we have carried out one of the first large scale (4611 individuals) GWAS on food likings assessed for 20 specific food likings belonging to 4 different categories (vegetables, fatty, dairy and bitter). A two-step meta-analysis using three different isolated populations from Italy for the discovery step and two populations from The Netherlands and Central Asia for replication, revealed 15 independent genome-wide significant loci (p < 5 × 10(-8)) for 12 different foods. None of the identified genes coded for either taste or olfactory receptors suggesting that genetics impacts in determining food likings in a much broader way than simple differences in taste perception. These results represent a further step in uncovering the genes that underlie liking of common foods that in the end will greatly help understanding the genetics of human nutrition in general.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11154-016-9354-3DOI Listing
June 2016

Understanding the role of personality and alexithymia in food preferences and PROP taste perception.

Physiol Behav 2016 Apr 22;157:72-8. Epub 2016 Jan 22.

Department of Food Science, School of Environmental and Biological Sciences, Rutgers University, 65 Dudley Road, New Brunswick, NJ 08901, USA. Electronic address:

Taste perception and food preferences are influenced by a variety of factors, including personality characteristics. The aims of this study were to examine the role of personality characteristics, such as alexithymia (a personality construct characterized by inability to identify, describe, and work with one's own feelings), in: 1) taste responses to the bitter genetic taste-marker PROP and 2) food liking. We studied 649 healthy subjects residing in six genetically-isolated villages of Northeast Italy. Data on PROP taste responsiveness, food liking, personality characteristics and TAS2R28 genotypes were collected. Results showed that PROP non-tasters had higher alexithymia scores than PROP tasters. Moreover, the presence of alexithymia in heterozygous individuals for the rs1726886 polymorphism of the TAS2R38 gene was associated with a reduction in the perceived intensity of PROP. Finally, higher alexithymia scores were associated with liking of alcohol, sweets and fats/meats whereas lower alexithymia scores were related to liking of vegetables, condiments and strong cheeses, Measures of temperament, character, anxiety and depression were also related to food liking. Our findings suggest that: 1) alexithymia, in addition to the TAS2R38 polymorphism, may play a role in responsiveness to the aversive and bitter taste of PROP; and 2) alexithymia, in combination with other personality traits, may provide important insights for better understanding food liking.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.physbeh.2016.01.022DOI Listing
April 2016

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Nat Genet 2015 Nov 28;47(11):1294-1303. Epub 2015 Sep 28.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661791PMC
November 2015

Food Preference Patterns in a UK Twin Cohort.

Twin Res Hum Genet 2015 Dec 28;18(6):793-805. Epub 2015 Sep 28.

Department of Twin Research and Genetic Epidemiology,King's College London,London,UK.

Food liking-disliking patterns may strongly influence food choices and health. Here we assess: (1) whether food preference patterns are genetic/environmentally driven; and (2) the relationship between metabolomics profiles and food preference patterns in a large population of twins. 2,107 individuals from TwinsUK completed an online food and lifestyle preference questionnaire. Principle components analysis was undertaken to identify patterns of food liking-disliking. Heritability estimates for each liking pattern were obtained by structural equation modeling. The correlation between blood metabolomics profiles (280 metabolites) and each food liking pattern was assessed in a subset of 1,491 individuals and replicated in an independent subset of monozygotic twin pairs discordant for the liking pattern (65 to 88 pairs). Results from both analyses were meta-analyzed. Four major food-liking patterns were identified (Fruit and Vegetable, Distinctive Tastes, Sweet and High Carbohydrate, and Meat) accounting for 26% of the total variance. All patterns were moderately heritable (Fruit and Vegetable, h(2)[95% CI]: 0.36 [0.28; 0.44]; Distinctive Tastes: 0.58 [0.52; 0.64]; Sweet and High Carbohydrate: 0.52 [0.45, 0.59] and Meat: 0.44 [0.35; 0.51]), indicating genetic factors influence food liking-disliking. Overall, we identified 14 significant metabolite associations (Bonferroni p < 4.5 × 10(-5)) with Distinctive Tastes (8 metabolites), Sweet and High Carbohydrate (3 metabolites), and Meat (3 metabolites). Food preferences follow patterns based on similar taste and nutrient characteristics and these groupings are strongly determined by genetics. Food preferences that are strongly genetically determined (h(2) ≥ 0.40), such as for meat and distinctive-tasting foods, may influence intakes more substantially, as demonstrated by the metabolomic associations identified here.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/thg.2015.69DOI Listing
December 2015

Polymorphisms in sweet taste genes (TAS1R2 and GLUT2), sweet liking, and dental caries prevalence in an adult Italian population.

Genes Nutr 2015 Sep 13;10(5):485. Epub 2015 Aug 13.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65/1, 34137, Trieste, Italy,

The aim of the study was to assess the relationship between sweet taste genes and dental caries prevalence in a large sample of adults. In addition, the association between sweet liking and sugar intake with dental caries was investigated. Caries was measured by the decayed, missing, filled teeth (DMFT) index in 647 Caucasian subjects (285 males and 362 females, aged 18-65 years), coming from six villages in northeastern Italy. Sweet liking was assessed using a 9-point scale, and the mean of the liking given by each individual to specific sweet food and beverages was used to create a sweet liking score. Simple sugar consumption was estimated by a dietary history interview, considering both added sugars and sugar present naturally in foods. Our study confirmed that polymorphisms in TAS1R2 and GLUT2 genes are related to DMFT index. In particular, GG homozygous individuals for rs3935570 in TAS1R2 gene (p value = 0.0117) and GG homozygous individuals for rs1499821 in GLUT2 gene (p value = 0.0273) showed higher DMFT levels compared to both heterozygous and homozygous for the alternative allele. Furthermore, while the relationship sugar intake-DMFT did not achieve statistical significance (p value = 0.075), a significant association was identified between sweet liking and DMFT (p value = 0.004), independent of other variables. Our study showed that sweet taste genetic factors contribute to caries prevalence and highlighted the role of sweet liking as a predictor of caries risk. Therefore, these results may open new perspectives for individual risk identification and implementation of target preventive strategies, such as identifying high-risk patients before caries development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12263-015-0485-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534477PMC
September 2015

Multicohort analysis of the maternal age effect on recombination.

Nat Commun 2015 Aug 5;6:7846. Epub 2015 Aug 5.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX17BN, UK.

Several studies have reported that the number of crossovers increases with maternal age in humans, but others have found the opposite. Resolving the true effect has implications for understanding the maternal age effect on aneuploidies. Here, we revisit this question in the largest sample to date using single nucleotide polymorphism (SNP)-chip data, comprising over 6,000 meioses from nine cohorts. We develop and fit a hierarchical model to allow for differences between cohorts and between mothers. We estimate that over 10 years, the expected number of maternal crossovers increases by 2.1% (95% credible interval (0.98%, 3.3%)). Our results are not consistent with the larger positive and negative effects previously reported in smaller cohorts. We see heterogeneity between cohorts that is likely due to chance effects in smaller samples, or possibly to confounders, emphasizing that care should be taken when interpreting results from any specific cohort about the effect of maternal age on recombination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms8846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580993PMC
August 2015

Uncovering the genetic basis for food preferences: the key to personalized nutrition plans?

Per Med 2015 Aug;12(4):315-317

Medical Genetics, Institute for Maternal & Child Health IRCCS 'Burlo Garofolo', 34100 Trieste, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pme.15.12DOI Listing
August 2015

Directional dominance on stature and cognition in diverse human populations.

Nature 2015 Jul 1;523(7561):459-462. Epub 2015 Jul 1.

Department of Nutrition and Dietetics, Harokopio University of Athens, 70, El. Venizelou Ave, Athens, 17671, Greece.

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature14618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516141PMC
July 2015

Modulation of genetic associations with serum urate levels by body-mass-index in humans.

PLoS One 2015 26;10(3):e0119752. Epub 2015 Mar 26.

Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom; Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom.

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119752PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374966PMC
March 2016

Genome-wide association analysis on five isolated populations identifies variants of the HLA-DOA gene associated with white wine liking.

Eur J Hum Genet 2015 Dec 11;23(12):1717-22. Epub 2015 Mar 11.

Institute for Maternal and Child Health, IRCCS, Burlo, Garofolo.

Wine is the most popular alcoholic beverage around the world and because of its importance in society has been widely studied. Understanding what drives its flavor has been a quest for decades but much is still unknown and will be determined at least in part by individual taste preferences. Recently studies in the genetics of taste have uncovered the role of different genes in the determination of food preferences giving new insight on its physiology. In this context we have performed a genome-wide association study on red and white wine liking using three isolated populations collected in Italy, and replicated our results on two additional populations coming from the Netherland and Central Asia for a total of 3885 samples. We have found a significant association (P=2.1 × 10(-8)) between white wine liking and rs9276975:C>T a polymorphism in the HLA-DOA gene encoding a non-canonical MHC II molecule, which regulates other MHC II molecules. The same association was also found with red wine liking (P=8.3 × 10(-6)). Sex-separated analysis have also revealed that the effect of HLA-DOA is twice as large in women as compared to men suggesting an interaction between this polymorphism and gender. Our results are one of the first examples of genome-wide association between liking of a commonly consumed food and gene variants. Moreover, our results suggest a role of the MHC system in the determination of food preferences opening new insight in this field in general.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2015.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795214PMC
December 2015

Genetic landscape of populations along the Silk Road: admixture and migration patterns.

BMC Genet 2014 Dec 5;15:131. Epub 2014 Dec 5.

Institute of Genetics and Biophysics 'A. Buzzati-Traverso', National Research Council (CNR), via Pietro Castellino 111, 80131, Naples, Italy.

Background: The ancient Silk Road has been a trading route between Europe and Central Asia from the 2(nd) century BCE to the 15(th) century CE. While most populations on this route have been characterized, the genetic background of others remains poorly understood, and little is known about past migration patterns. The scientific expedition "Marco Polo" has recently collected genetic and phenotypic data in six regions (Georgia, Armenia, Azerbaijan, Uzbekistan, Kazakhstan, Tajikistan) along the Silk Road to study the genetics of a number of phenotypes.

Results: We characterized the genetic structure of these populations within a worldwide context. We observed a West-East subdivision albeit the existence of a genetic component shared within Central Asia and nearby populations from Europe and Near East. We observed a contribution of up to 50% from Europe and Asia to most of the populations that have been analyzed. The contribution from Asia dates back to ~25 generations and is limited to the Eastern Silk Road. Time and direction of this contribution are consistent with the Mongolian expansion era.

Conclusions: We clarified the genetic structure of six populations from Central Asia and suggested a complex pattern of gene flow among them. We provided a map of migration events in time and space and we quantified exchanges among populations. Altogether these novel findings will support the future studies aimed at understanding the genetics of the phenotypes that have been collected during the Marco Polo campaign, they will provide insights into the history of these populations, and they will be useful to reconstruct the developments and events that have shaped modern Eurasians genomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12863-014-0131-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267745PMC
December 2014
-->