Publications by authors named "Eleonora Porcu"

63 Publications

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.

Nat Genet 2021 Sep 2;53(9):1300-1310. Epub 2021 Sep 2.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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http://dx.doi.org/10.1038/s41588-021-00913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432599PMC
September 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Self-efficacy, coping strategies and quality of life in women and men requiring assisted reproductive technology treatments for anatomical or non-anatomical infertility.

Eur J Obstet Gynecol Reprod Biol 2021 Sep 21;264:241-246. Epub 2021 Jul 21.

Infertility and IVF Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; University of Bologna - DIMEC, Bologna, Italy.

Objective: To examine the magnitude and the predictors of emotional reactions to an infertility diagnosis, comparing women and men who were clinically diagnosed with an anatomical cause of infertility or non-anatomical cause of infertility.

Study Design: Cross-sectional study involving a total of 133 adults waiting for infertility treatment at the IVF and Infertility Unit of the S. Orsola University Hospital in Bologna (Italy). Of these, 107 patients (55 with anatomical causes of infertility and 52 with non-anatomical causes of infertility; response rate: 80%) took part to the study. After providing informed written consent, each participant was asked to complete the Infertility Self-efficacy Scale, the Fertility Quality of Life, and the Brief Coping Orientation to Problem Experienced, which they returned at their second access to the Unit. Differences between the groups were analyzed through a series of univariate ANOVA, whereas a multiple regression analysis was used to jointly examine the predictors of fertility quality of life.

Results: Results showed both gender related and diagnosis related differences. Women had statistically significant lower scores than men on the Infertility Self-Efficacy Scale and on the global, emotional, and mind-body subscales of the Fertility Quality of Life, while they scored significantly higher on the emotion focused and socially supported subscales of the Coping Orientation to Problem Experienced. Independently of gender, patients with non-anatomical causes of infertility scored poorly than patients with anatomical causes of infertility on the relational subscale of the Fertility Quality of Life and on the Avoidant scale of the Brief Coping Orientation to Problem Experienced. Hierarchical multiple regression analyses revealed that higher levels of self-efficacy and a lower use of avoidant coping strategies predicted a more positive quality of life over and above gender and cause of infertility.

Conclusion: This study partly confirms data on gender differences in experiencing the psychological burden of infertility and adds some new information, particularly with respect to the prediction of quality of life indicators over and above infertility cause.
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http://dx.doi.org/10.1016/j.ejogrb.2021.07.027DOI Listing
September 2021

Two subsequent seminal productions: A good strategy to treat very severe oligoasthenoteratozoospermic infertile couples.

Andrology 2021 07 28;9(4):1185-1191. Epub 2021 Apr 28.

Infertility and IVF Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Background: Sexual abstinence is considered one of the several factors that influence sperm quality. Recent studies show that a shortening of the abstinence period could be beneficial mostly in oligoasthenoteratozoospermic (OAT) patients.

Objective: Retrospective study to verify the efficacy of a second semen sample after a short abstinence to treat severe OAT infertile patients.

Materials And Methods: 127 couples treated between May 2014 and May 2018 were divided into two groups. Study Group 1 (75 cycles): severe OAT characteristics: count <0.2 × 10 /mL no progressive motility; count ≥0.2 × 10 /mL and no total or progressive motility; 0% normal morphology; a second semen sample was requested after abstinence of 2 h. Control Group 0 (52 cycles): normozoospermic or mild OAT; only one sample was requested. Intracytoplasmic sperm injection was utilized in all cases.

Results: All semen parameters were significantly different between Group 0 vs both samples of Group 1 (p < 0.001), excluding volume between Group 0 and 1st sample of Group 1 (p = 0.682). The comparison between 1st and 2nd samples from Group 1 showed significant differences in volume, total and progressive motility and morphology (p < 0.001, p < 0.001, p < 0.020) but not in total sperm count (p = 0.970). Fertilization, pregnancy rate/transfer, implantation and miscarriage rates were 85.9% and 61.1% (p < 0.001), 30.6% and 35.8% (p = 0.700), 17.5% and 24.0 (p = 0.292), 20.0% and 25.0% (p = 0.017) in Group 0 and Group 1 respectively.

Discussion And Conclusion: The results show that a short abstinence in severe OAT patients allows us to obtain spermatozoa with better motility. The request for a second semen sample in couples with extreme semen parameters is a valid and simple strategy that helps to achieve the same probability of pregnancy compared to a Control Group. Furthermore, it allows us to utilize fresh spermatozoa avoiding the need to resort to cryopreserved reserves or testicular surgery.
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http://dx.doi.org/10.1111/andr.13020DOI Listing
July 2021

Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes.

Sci Rep 2021 03 18;11(1):6197. Epub 2021 Mar 18.

Swiss Institute of Bioinformatics, Lausanne, Switzerland.

The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.
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http://dx.doi.org/10.1038/s41598-021-85684-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973501PMC
March 2021

mutation alters immune system activation, inflammation, and risk of autoimmunity.

Mult Scler 2021 Aug 14;27(9):1332-1340. Epub 2020 Oct 14.

Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Monserrato, Italy.

Background: Defective alleles within the gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines-cytokine storm.

Objective: The aim of this study was to determine the function of hypomorph g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D).

Methods: We cross-compare the association data for mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians.

Results: We report that , is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia  = 2.06 × 10, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D  = 1.04 × 10, OR = 0.82.

Conclusion: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis.
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http://dx.doi.org/10.1177/1352458520963937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044257PMC
August 2021

Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two cohort studies.

Sci Rep 2021 Feb 4;11(1):3100. Epub 2021 Feb 4.

Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland.

Individuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation.
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http://dx.doi.org/10.1038/s41598-021-82714-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862626PMC
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

High-security closed devices are efficient and safe to protect human oocytes from potential risk of viral contamination during vitrification and storage especially in the COVID-19 pandemic.

J Assist Reprod Genet 2021 Mar 11;38(3):681-688. Epub 2021 Jan 11.

Infertility and IVF Unit, University of Bologna, Sant'Orsola University Hospital, Bologna, Italy.

Purpose: The main purpose and research question of the study are to compare the efficacy of high-security closed versus open devices for human oocytes' vitrification.

Methods: A prospective randomized study was conducted. A total of 737 patients attending the Infertility and IVF Unit at S.Orsola University Hospital (Italy) between October 2015 and April 2020 were randomly assigned to two groups. A total of 368 patients were assigned to group 1 (High-Security Vitrification™ - HSV) and 369 to group 2 (Cryotop® open system). Oocyte survival, fertilization, cleavage, pregnancy, implantation, and miscarriage rate were compared between the two groups.

Results: No statistically significant differences were observed on survival rate (70.3% vs. 73.3%), fertilization rate (70.8% vs. 74.9%), cleavage rate (90.6% vs. 90.3%), pregnancy/transfer ratio (32.0% vs. 31.8%), implantation rate (19.7% vs. 19.9%), nor miscarriage rates (22.1% vs. 21.5%) between the two groups. Women's mean age in group 1 (36.18 ± 3.92) and group 2 (35.88 ± 3.88) was not significantly different (P = .297). A total of 4029 oocytes were vitrified (1980 and 2049 in groups 1 and 2 respectively). A total of 2564 were warmed (1469 and 1095 in groups 1 and 2 respectively). A total of 1386 morphologically eligible oocytes were inseminated by intracytoplasmic sperm injection (792 and 594 respectively, P = .304).

Conclusions: The present study shows that the replacement of the open vitrification system by a closed one has no impact on in vitro and in vivo survival, development, pregnancy and implantation rate. Furthermore, to ensure safety, especially during the current COVID-19 pandemic, the use of the closed device eliminates the potential samples' contamination during vitrification and storage.
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http://dx.doi.org/10.1007/s10815-021-02062-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799863PMC
March 2021

Causal Inference Methods to Integrate Omics and Complex Traits.

Cold Spring Harb Perspect Med 2021 05 3;11(5). Epub 2021 May 3.

Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.

Major biotechnological advances have facilitated a tremendous boost to the collection of (gen-/transcript-/prote-/methyl-/metabol-)omics data in very large sample sizes worldwide. Coordinated efforts have yielded a deluge of studies associating diseases with genetic markers (genome-wide association studies) or with molecular phenotypes. Whereas omics-disease associations have led to biologically meaningful and coherent mechanisms, the identified (non-germline) disease biomarkers may simply be correlates or consequences of the explored diseases. To move beyond this realm, Mendelian randomization provides a principled framework to integrate information on omics- and disease-associated genetic variants to pinpoint molecular traits causally driving disease development. In this review, we show the latest advances in this field, flag up key challenges for the future, and propose potential solutions.
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http://dx.doi.org/10.1101/cshperspect.a040493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091955PMC
May 2021

Impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes in young women with breast cancer.

J Assist Reprod Genet 2020 Mar 24;37(3):709-715. Epub 2019 Dec 24.

Infertility and IVF Unit, University of Bologna, Sant'Orsola - Malpighi University Hospital, Via Massarenti 13, 40138 University of Bologna, Bologna, Italy.

Purpose: To determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcome. The main purpose and research question of the study is to determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes.

Methods: Prospective study: 67 breast cancer patients between 18 and 40 years old, undergoing a fertility preservation by means of oocyte storage were considered. Inclusions criteria for the study were age between 18 and 40 years old, BMI between 18 and 28, breast cancer neoplasm stage I and II according to American Joint Committee on Cancer classification (2017) and no metastasis.

Exclusion Criteria: age over 40 years old, BMI < 18 and > 28, breast cancer neoplasm stage III and IV and do not performed the BRCA test. A total of 21 patients had not performed the test and were excluded. Patients were divided into four groups: Group A was composed by 11 breast cancer patients with BRCA 1 mutations, Group B was composed by 11 breast cancer patients with BRCA 2 mutations, Group C was composed by 24 women with breast cancer without BRCA mutations, and Group D (control) was composed by 181 normal women.

Results: Group A showed significant lower AMH levels compared to Group C and D (1.2 ± 1.1 vs 4.5 ± 4.1 p < 0.05 and 1.2 ± 1.1 vs 3.8 ± 2.5 p < 0.05). BRCA1 mutated patients showed a significant lower rate of mature oocytes (MII) compared to Group C (3.1 ± 2.3 vs 7.2 ± 4.4 p < 0,05) and Group D (3.1 ± 2.3 vs 7.3 ± 3.4; p < 0,05). Breast cancer patients needed a higher dose of gonadotropins compared to controls (Group A 2206 ± 1392 Group B2047.5 ± 829.9 Group C 2106 ± 1336 Group D 1597 ± 709 p < 0,05). No significant differences were found among the groups considering basal FSH levels, duration of stimulation, number of developed follicles, and number of total retrieved oocytes. Regarding BRCA2 mutation, no effect on fertility was shown in this study.

Conclusions: The study showed that BRCA1 patients had a higher risk of premature ovarian insufficiency (POI) confirmed by a diminished ovarian reserve and a lower number of mature oocytes suitable for cryopreservation.
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http://dx.doi.org/10.1007/s10815-019-01658-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125060PMC
March 2020

The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals.

Am J Hum Genet 2019 11 24;105(5):947-958. Epub 2019 Oct 24.

Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland.

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e-7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2 and Bola2 animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849090PMC
November 2019

Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits.

Nat Commun 2019 07 24;10(1):3300. Epub 2019 Jul 24.

Swiss Institute of Bioinformatics, Lausanne, Switzerland.

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene-trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
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http://dx.doi.org/10.1038/s41467-019-10936-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656778PMC
July 2019

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Nat Commun 2018 10 26;9(1):4455. Epub 2018 Oct 26.

Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
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http://dx.doi.org/10.1038/s41467-018-06356-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203810PMC
October 2018

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

Bayesian association scan reveals loci associated with human lifespan and linked biomarkers.

Nat Commun 2017 07 27;8:15842. Epub 2017 Jul 27.

Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne 1010, Switzerland.

The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR). Eleven of them replicate (5% FDR) in five independent longevity studies combined; all but three are depleted of the life-shortening alleles in older Biobank participants. Further analysis revealed that brain expression levels of nearby genes (RBM6, SULT1A1 and CHRNA5) might be causally implicated in longevity. Gene expression and caloric restriction experiments in model organisms confirm the conserved role for RBM6 and SULT1A1 in modulating lifespan.
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http://dx.doi.org/10.1038/ncomms15842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537485PMC
July 2017

Overexpression of the Cytokine BAFF and Autoimmunity Risk.

N Engl J Med 2017 04;376(17):1615-1626

From Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (M.S., V.O., M.L.I., M. Pitzalis, M. Pala, C.S., V.F., M.F., M. Deiana, I.A., E.P., A. Mulas, M.G.P., M. Lobina, S.L., Mara Marongiu, V.S., Michele Marongiu, G.S., F.B., A. Maschio, F.D., M. Dei, F.V., S.O., A.A., M.B.W., A. Meloni, S. Sanna, E.F., M.Z., F.C.), Center for Advanced Studies, Research, and Development in Sardinia, Parco Scientifico e Tecnologico della Sardegna (I.Z., M.F., R.C., G. Cuccuru), Struttura Complessa Disciplina di Ematologia e Centro Trapianto Cellule Staminali Emopoietiche Wilma Deplano, Ospedale Oncologico di Riferimento Regionale Armando Businco (M. Pani), Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università di Cagliari (E.C., J.F., G. Coghe, L.L., G. Fenu), Azienda Ospedaliera Brotzu, S.C. Neurologia (P.F., M. Melis), Division of Rheumatology, University and University Hospital of Cagliari (M. Piga, A. Mathieu), Department of Medical Sciences M. Aresu, University of Cagliari (D.F., S.D.G., M.G.M.), Azienda Ospedaliera Brotzu, U.S. Gastroenterologia Pediatrica Ospedale Pediatrico Microcitemico A. Cao (M.C.), and Nephrology, Dialysis, and Transplantation Unit, Giuseppe Brotzu Hospital (A.P.), Cagliari, Dipartimento di Scienze Biomediche, Università degli Studi di Sassari (M.F., F.P., F.C.), Unit of Neurology, Department of Clinical and Experimental Medicine, University of Sassari (G. Farina, G.R.), and Servizio Trasfusionale (M.A.S.) and Clinica Medica (A.D.), Azienda Ospedaliero Universitaria di Sassari, Sassari, Neurology B, Department of Neurological, Biomedical, and Movement Sciences, University of Verona, Verona (G. Farina), Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont, Novara (N.B., S.D.), SC Neurologia, Dipartimento di Scienze Mediche, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo (M. Leone), Don C. Gnocchi Foundation IRCCS (F.R.G.), and Referral Center for Systemic Autoimmune Diseases Fondazione IRCCS Cá Granda Ospedale Maggiore Policlinico and University of Milan (M. Marchini), Milan, and Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche e Ospedali Riuniti, Ancona (M.G.D.) - all in Italy; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore (M.L.I., M.G., D.S.); the Department of Clinical Neurosciences (M.B., S. Sawcer) and JDRF-Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research (J.A.T.), University of Cambridge, Cambridge, United Kingdom; Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital Solna (I.K., I.L.B., T.O., J.H.), Institute of Environmental Medicine (L.A.) and Institute of Environmental Medicine, Unit of Immunology and Chronic Disease (M.E.A.R.), Karolinska Institute, and Center for Occupational and Environmental Medicine, Stockholm County Council (L.A.), Stockholm; Department of Functional Biology, University of Oviedo, Oviedo (A.S.), Rheumatology Department, Hospital Universitario 12 de Octubre, Madrid (P.E.C.), Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Seville (M.J.C.-P.), Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela (A.G.), and Centro de Genómica e Investigación Oncológica, Pfizer-Universidad de Granada-Junta de Andalucía, Granada (M.E.A.R.) - all in Spain; Department of Human Genetics, University of Chicago, Chicago (J.H.M., J.N.); Centro Hospitalar do Porto-Hospital Santo Antonio and Unit for Multidisciplinary Research in Biomedicine-Unidade Multidisciplinar de Investigação Biomédica, Porto, Portugal (B.M.S.); Departments of Pathology and Genetics, Stanford University, Stanford, CA (S.B.M.); and Center for Statistical Genetics, University of Michigan, Ann Arbor (G.R.A.).

Background: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways.

Methods: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated.

Results: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria.

Conclusions: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).
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http://dx.doi.org/10.1056/NEJMoa1610528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605835PMC
April 2017

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Nat Genet 2017 Jun 24;49(6):834-841. Epub 2017 Apr 24.

Institute of Genetics and Biophysics, CNR, Naples, Italy.

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
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http://dx.doi.org/10.1038/ng.3841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841952PMC
June 2017

Bridging the gap: metabolic and endocrine care of patients during transition.

Endocr Connect 2016 Nov 1;5(6):R44-R54. Epub 2016 Nov 1.

Hôpital des EnfantsToulouse, France.

Objective: Seamless transition of endocrine patients from the paediatric to adult setting is still suboptimal, especially in patients with complex disorders, i.e., small for gestational age, Turner or Prader-Willi syndromes; Childhood Cancer Survivors, and those with childhood-onset growth hormone deficiency.

Methods: An expert panel meeting comprised of European paediatric and adult endocrinologists was convened to explore the current gaps in managing the healthcare of patients with endocrine diseases during transition from paediatric to adult care settings.

Results: While a consensus was reached that a team approach is best, discussions revealed that a 'one size fits all' model for transition is largely unsuccessful in these patients. They need more tailored care during adolescence to prevent complications like failure to achieve target adult height, reduced bone mineral density, morbid obesity, metabolic perturbations (obesity and body composition), inappropriate/inadequate puberty, compromised fertility, diminished quality of life and failure to adapt to the demands of adult life. Sometimes it is difficult for young people to detach emotionally from their paediatric endocrinologist and/or the abrupt change from an environment of parental responsibility to one of autonomy. Discussions about impending transition and healthcare autonomy should begin in early adolescence and continue throughout young adulthood to ensure seamless continuum of care and optimal treatment outcomes.

Conclusions: Even amongst a group of healthcare professionals with a great interest in improving transition services for patients with endocrine diseases, there is still much work to be done to improve the quality of healthcare for transition patients.
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http://dx.doi.org/10.1530/EC-16-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118971PMC
November 2016

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

Nat Genet 2016 12 31;48(12):1462-1472. Epub 2016 Oct 31.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
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http://dx.doi.org/10.1038/ng.3698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695684PMC
December 2016

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Sci Adv 2016 06 17;2(6):e1501678. Epub 2016 Jun 17.

Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, 35043 Marburg, Germany.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.
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http://dx.doi.org/10.1126/sciadv.1501678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928990PMC
June 2016

The burden of multiple sclerosis variants in continental Italians and Sardinians.

Mult Scler 2015 Oct;21(11):1385-95

Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy.

Background: Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored.

Objective: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians.

Methods: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves.

Results: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles.

Conclusions: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics.
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http://dx.doi.org/10.1177/1352458515596599DOI Listing
October 2015

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

Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers.

Nat Genet 2015 Nov 14;47(11):1272-1281. Epub 2015 Sep 14.

Human Genetics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1HH.

We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.
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http://dx.doi.org/10.1038/ng.3368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627508PMC
November 2015

Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels.

Nat Genet 2015 Nov 14;47(11):1264-71. Epub 2015 Sep 14.

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.

We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.
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http://dx.doi.org/10.1038/ng.3307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627580PMC
November 2015

Rare coding variants and X-linked loci associated with age at menarche.

Nat Commun 2015 Aug 4;6:7756. Epub 2015 Aug 4.

Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
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http://dx.doi.org/10.1038/ncomms8756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538850PMC
August 2015

The impact of assisted reproductive technology and chorionicity in twin pregnancies complicated by obstetric cholestasis.

J Matern Fetal Neonatal Med 2016 5;29(9):1481-4. Epub 2015 Jun 5.

d Department of Obstetrics and Gynecology , Maggiore Hospital, University of Parma , Parma, Italy.

Objective: To assess in a cohort of twin pregnancies the prevalence of obstetric cholestasis (OC) and its correlation with the type of conception and chorionicity.

Methods: A retrospective cohort study including all the twin pregnancies delivered between 2005 and 2013 at our University Hospital was carried out. In the study population, the prevalence of OC was investigated in relationship to the impact of assisted reproductive technology (ART) and of chorionicity.

Results: Overall, 569 twin pregnancies were included in the study population. Among those complicated by OC, the rate of ART was 3-fold higher (OR 3.4, 95% CI 1.2-9.5, p = 0.02), whereas the rate of dichorionicity did not differ significantly (OR 1.6, 95% CI 0.3-7.9, p = 0.53).

Conclusion: The risk of developing OC seems to be significantly higher among twin pregnancies obtained after ART in comparison with those conceived spontaneously.
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http://dx.doi.org/10.3109/14767058.2015.1051954DOI Listing
December 2016

Genome-wide association study of susceptibility loci for breast cancer in Sardinian population.

BMC Cancer 2015 May 10;15:383. Epub 2015 May 10.

Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Traversa La Crucca 3, Baldinca Li Punti, 07100, Sassari, Italy.

Background: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles.

Methods: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs.

Results: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p <  0(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16 x 10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts.

Conclusions: This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.
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http://dx.doi.org/10.1186/s12885-015-1392-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434540PMC
May 2015
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