Publications by authors named "Carlo Sidore"

46 Publications

Analysis of overlapping genetic association in type 1 and type 2 diabetes.

Diabetologia 2021 Jun 8;64(6):1342-1347. Epub 2021 Apr 8.

JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Aims/hypothesis: Given the potential shared aetiology between type 1 and type 2 diabetes, we aimed to identify any genetic regions associated with both diseases. For associations where there is a shared signal and the allele that increases risk to one disease also increases risk to the other, inference about shared aetiology could be made, with the potential to develop therapeutic strategies to treat or prevent both diseases simultaneously. Alternatively, if a genetic signal co-localises with divergent effect directions, it could provide valuable biological insight into how the association affects the two diseases differently.

Methods: Using publicly available type 2 diabetes summary statistics from a genome-wide association study (GWAS) meta-analysis of European ancestry individuals (74,124 cases and 824,006 controls) and type 1 diabetes GWAS summary statistics from a meta-analysis of studies on individuals from the UK and Sardinia (7467 cases and 10,218 controls), we identified all regions of 0.5 Mb that contained variants associated with both diseases (false discovery rate <0.01). In each region, we performed forward stepwise logistic regression to identify independent association signals, then examined co-localisation of each type 1 diabetes signal with each type 2 diabetes signal using coloc. Any association with a co-localisation posterior probability of ≥0.9 was considered a genuine shared association with both diseases.

Results: Of the 81 association signals from 42 genetic regions that showed association with both type 1 and type 2 diabetes, four association signals co-localised between both diseases (posterior probability ≥0.9): (1) chromosome 16q23.1, near CTRB1/BCAR1, which has been previously identified; (2) chromosome 11p15.5, near the INS gene; (3) chromosome 4p16.3, near TMEM129 and (4) chromosome 1p31.3, near PGM1. In each of these regions, the effect of genetic variants on type 1 diabetes was in the opposite direction to the effect on type 2 diabetes. Use of additional datasets also supported the previously identified co-localisation on chromosome 9p24.2, near the GLIS3 gene, in this case with a concordant direction of effect.

Conclusions/interpretation: Four of five association signals that co-localise between type 1 diabetes and type 2 diabetes are in opposite directions, suggesting a complex genetic relationship between the two diseases.
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http://dx.doi.org/10.1007/s00125-021-05428-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099827PMC
June 2021

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

Mult Scler 2020 Oct 14:1352458520963937. 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
October 2020

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

Complex genetic signatures in immune cells underlie autoimmunity and inform therapy.

Nat Genet 2020 10 14;52(10):1036-1045. Epub 2020 Sep 14.

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

We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.
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http://dx.doi.org/10.1038/s41588-020-0684-4DOI Listing
October 2020

Evidence of Polygenic Adaptation in Sardinia at Height-Associated Loci Ascertained from the Biobank Japan.

Am J Hum Genet 2020 07 12;107(1):60-71. Epub 2020 Jun 12.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Quantitative and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA. Electronic address:

Adult height is one of the earliest putative examples of polygenic adaptation in humans. However, this conclusion was recently challenged because residual uncorrected stratification from large-scale consortium studies was considered responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population. We re-examined this question, focusing on one of the shortest European populations, the Sardinians, in addition to mainland European populations. We utilized height-associated loci from the Biobank Japan (BBJ) dataset to further alleviate concerns of biased ascertainment of GWAS loci and showed that the Sardinians remain significantly shorter than expected under neutrality (∼0.22 standard deviation shorter than Utah residents with ancestry from northern and western Europe [CEU] on the basis of polygenic height scores, p = 3.89 × 10). We also found the trajectory of polygenic height scores between the Sardinian and the British populations diverged over at least the last 10,000 years (p = 0.0082), consistent with a signature of polygenic adaptation driven primarily by the Sardinian population. Although the polygenic score-based analysis showed a much subtler signature in mainland European populations, we found a clear and robust adaptive signature in the UK population by using a haplotype-based statistic, the trait singleton density score (tSDS), driven by the height-increasing alleles (p = 9.1 × 10). In summary, by ascertaining height loci in a distant East Asian population, we further supported the evidence of polygenic adaptation at height-associated loci among the Sardinians. In mainland Europeans, the adaptive signature was detected in haplotype-based analysis but not in polygenic score-based analysis.
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http://dx.doi.org/10.1016/j.ajhg.2020.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332648PMC
July 2020

Sequencing and imputation in GWAS: Cost-effective strategies to increase power and genomic coverage across diverse populations.

Genet Epidemiol 2020 09 9;44(6):537-549. Epub 2020 Jun 9.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan.

A key aim for current genome-wide association studies (GWAS) is to interrogate the full spectrum of genetic variation underlying human traits, including rare variants, across populations. Deep whole-genome sequencing is the gold standard to fully capture genetic variation, but remains prohibitively expensive for large sample sizes. Array genotyping interrogates a sparser set of variants, which can be used as a scaffold for genotype imputation to capture a wider set of variants. However, imputation quality depends crucially on reference panel size and genetic distance from the target population. Here, we consider sequencing a subset of GWAS participants and imputing the rest using a reference panel that includes both sequenced GWAS participants and an external reference panel. We investigate how imputation quality and GWAS power are affected by the number of participants sequenced for admixed populations (African and Latino Americans) and European population isolates (Sardinians and Finns), and identify powerful, cost-effective GWAS designs given current sequencing and array costs. For populations that are well-represented in existing reference panels, we find that array genotyping alone is cost-effective and well-powered to detect common- and rare-variant associations. For poorly represented populations, sequencing a subset of participants is often most cost-effective, and can substantially increase imputation quality and GWAS power.
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http://dx.doi.org/10.1002/gepi.22326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449570PMC
September 2020

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.

Nat Commun 2020 03 30;11(1):1600. Epub 2020 Mar 30.

Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA.

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10 and OR = 3.39, P = 5.2 × 10, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.
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http://dx.doi.org/10.1038/s41467-020-15383-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105485PMC
March 2020

Genetic history from the Middle Neolithic to present on the Mediterranean island of Sardinia.

Nat Commun 2020 02 24;11(1):939. Epub 2020 Feb 24.

Department of History, Human Sciences and Education, University of Sassari, 07100, Sassari, Italy.

The island of Sardinia has been of particular interest to geneticists for decades. The current model for Sardinia's genetic history describes the island as harboring a founder population that was established largely from the Neolithic peoples of southern Europe and remained isolated from later Bronze Age expansions on the mainland. To evaluate this model, we generate genome-wide ancient DNA data for 70 individuals from 21 Sardinian archaeological sites spanning the Middle Neolithic through the Medieval period. The earliest individuals show a strong affinity to western Mediterranean Neolithic populations, followed by an extended period of genetic continuity on the island through the Nuragic period (second millennium BCE). Beginning with individuals from Phoenician/Punic sites (first millennium BCE), we observe spatially-varying signals of admixture with sources principally from the eastern and northern Mediterranean. Overall, our analysis sheds light on the genetic history of Sardinia, revealing how relationships to mainland populations shifted over time.
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http://dx.doi.org/10.1038/s41467-020-14523-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039977PMC
February 2020

Meta-MultiSKAT: Multiple phenotype meta-analysis for region-based association test.

Genet Epidemiol 2019 10 21;43(7):800-814. Epub 2019 Aug 21.

Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.

The power of genetic association analyses can be increased by jointly meta-analyzing multiple correlated phenotypes. Here, we develop a meta-analysis framework, Meta-MultiSKAT, that uses summary statistics to test for association between multiple continuous phenotypes and variants in a region of interest. Our approach models the heterogeneity of effects between studies through a kernel matrix and performs a variance component test for association. Using a genotype kernel, our approach can test for rare-variants and the combined effects of both common and rare-variants. To achieve robust power, within Meta-MultiSKAT, we developed fast and accurate omnibus tests combining different models of genetic effects, functional genomic annotations, multiple correlated phenotypes, and heterogeneity across studies. In addition, Meta-MultiSKAT accommodates situations where studies do not share exactly the same set of phenotypes or have differing correlation patterns among the phenotypes. Simulation studies confirm that Meta-MultiSKAT can maintain the type-I error rate at the exome-wide level of 2.5 × 10 . Further simulations under different models of association show that Meta-MultiSKAT can improve the power of detection from 23% to 38% on average over single phenotype-based meta-analysis approaches. We demonstrate the utility and improved power of Meta-MultiSKAT in the meta-analyses of four white blood cell subtype traits from the Michigan Genomics Initiative (MGI) and SardiNIA studies.
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http://dx.doi.org/10.1002/gepi.22248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006736PMC
October 2019

Parent-of-origin effects on quantitative phenotypes in a large Hutterite pedigree.

Commun Biol 2019 18;2:28. Epub 2019 Jan 18.

1Department of Human Genetics, University of Chicago, Chicago, IL 60637 USA.

The impact of the parental origin of associated alleles in GWAS has been largely ignored. Yet sequence variants could affect traits differently depending on whether they are inherited from the mother or the father, as in imprinted regions, where identical inherited DNA sequences can have different effects based on the parental origin. To explore parent-of-origin effects (POEs), we studied 21 quantitative phenotypes in a large Hutterite pedigree to identify variants with single parent (maternal-only or paternal-only) effects, and then variants with opposite parental effects. Here we show that POEs, which can be opposite in direction, are relatively common in humans, have potentially important clinical effects, and will be missed in traditional GWAS. We identified POEs with 11 phenotypes, most of which are risk factors for cardiovascular disease. Many of the loci identified are characteristic of imprinted regions and are associated with the expression of nearby genes.
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http://dx.doi.org/10.1038/s42003-018-0267-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338666PMC
April 2020

Relative impact of indels versus SNPs on complex disease.

Genet Epidemiol 2019 02 22;43(1):112-117. Epub 2018 Nov 22.

Center for Statistical Genetics, and Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.

It is unclear whether insertions and deletions (indels) are more likely to influence complex traits than abundant single-nucleotide polymorphisms (SNPs). We sought to understand which category of variation is more likely to impact health. Using the SardiNIA study as an exemplar, we characterized 478,876 common indels and 8,246,244 common SNPs in up to 5,949 well-phenotyped individuals from an isolated valley in Sardinia. We assessed association between 120 traits, resulting in 89 nonoverlapping-associated loci.We evaluated whether indels were enriched among credible sets of potential causal variants. These credible sets included 1,319 SNPs and 88 indels. We did not find indels to be significantly enriched. Indels were the most likely causal variant in seven loci, including one locus associated with monocyte count where an indel with causality and mechanism previously demonstrated (rs200748895:TGCTG/T) had a 0.999 posterior probability. Overall, our results show a very modest and nonsignificant enrichment for common indels in associated loci.
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http://dx.doi.org/10.1002/gepi.22175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330128PMC
February 2019

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Am J Hum Genet 2018 11;103(5):691-706

Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218410PMC
November 2018

Genomic history of the Sardinian population.

Nat Genet 2018 10 17;50(10):1426-1434. Epub 2018 Sep 17.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of genetic similarity with mainland ancient DNA samples varies subtly across the island. Together, our results indicate that within-island substructure and sex-biased processes have substantially impacted the genetic history of Sardinia. These results give new insight into the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations.
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http://dx.doi.org/10.1038/s41588-018-0215-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168346PMC
October 2018

XCAVATOR: accurate detection and genotyping of copy number variants from second and third generation whole-genome sequencing experiments.

BMC Genomics 2017 Sep 21;18(1):747. Epub 2017 Sep 21.

Istituto di Ricerca Genetica e Biomedica (IRGB), Cittadella Universitaria di Cagliari, Monserrato, 09042, Italy.

Background: We developed a novel software package, XCAVATOR, for the identification of genomic regions involved in copy number variants/alterations (CNVs/CNAs) from short and long reads whole-genome sequencing experiments.

Results: By using simulated and real datasets we showed that our tool, based on read count approach, is capable to predict the boundaries and the absolute number of DNA copies CNVs/CNAs with high resolutions. To demonstrate the power of our software we applied it to the analysis Illumina and Pacific Bioscencies data and we compared its performance to other ten state of the art tools.

Conclusion: All the analyses we performed demonstrate that XCAVATOR is capable to detect germline and somatic CNVs/CNAs outperforming all the other tools we compared. XCAVATOR is freely available at http://sourceforge.net/projects/xcavator/ .
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http://dx.doi.org/10.1186/s12864-017-4137-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609061PMC
September 2017

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.

Am J Hum Genet 2017 Jun 25;100(6):865-884. Epub 2017 May 25.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital NHS Trust, Middlesex UB1 3EU, UK.

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.
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http://dx.doi.org/10.1016/j.ajhg.2017.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473732PMC
June 2017

fastMitoCalc: an ultra-fast program to estimate mitochondrial DNA copy number from whole-genome sequences.

Bioinformatics 2017 05;33(9):1399-1401

Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA.

Availability And Implementation: fastMitoCalc is available at https://lgsun.irp.nia.nih.gov/hsgu/software/mitoAnalyzer/index.html.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btw835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860513PMC
May 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

Population- and individual-specific regulatory variation in Sardinia.

Nat Genet 2017 May 10;49(5):700-707. Epub 2017 Apr 10.

Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.

Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.
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http://dx.doi.org/10.1038/ng.3840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411016PMC
May 2017

Mitogenome Diversity in Sardinians: A Genetic Window onto an Island's Past.

Mol Biol Evol 2017 05;34(5):1230-1239

Department of Biological Sciences, School of Applied Sciences, University of Huddersfield, Huddersfield, Queensgate, United Kingdom.

Sardinians are "outliers" in the European genetic landscape and, according to paleogenomic nuclear data, the closest to early European Neolithic farmers. To learn more about their genetic ancestry, we analyzed 3,491 modern and 21 ancient mitogenomes from Sardinia. We observed that 78.4% of modern mitogenomes cluster into 89 haplogroups that most likely arose in situ. For each Sardinian-specific haplogroup (SSH), we also identified the upstream node in the phylogeny, from which non-Sardinian mitogenomes radiate. This provided minimum and maximum time estimates for the presence of each SSH on the island. In agreement with demographic evidence, almost all SSHs coalesce in the post-Nuragic, Nuragic and Neolithic-Copper Age periods. For some rare SSHs, however, we could not dismiss the possibility that they might have been on the island prior to the Neolithic, a scenario that would be in agreement with archeological evidence of a Mesolithic occupation of Sardinia.
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http://dx.doi.org/10.1093/molbev/msx082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400395PMC
May 2017

Next-generation genotype imputation service and methods.

Nat Genet 2016 10 29;48(10):1284-1287. Epub 2016 Aug 29.

Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.

Genotype imputation is a key component of genetic association studies, where it increases power, facilitates meta-analysis, and aids interpretation of signals. Genotype imputation is computationally demanding and, with current tools, typically requires access to a high-performance computing cluster and to a reference panel of sequenced genomes. Here we describe improvements to imputation machinery that reduce computational requirements by more than an order of magnitude with no loss of accuracy in comparison to standard imputation tools. We also describe a new web-based service for imputation that facilitates access to new reference panels and greatly improves user experience and productivity.
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http://dx.doi.org/10.1038/ng.3656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157836PMC
October 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.
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http://dx.doi.org/10.1038/ng.3643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388176PMC
October 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

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

Height-reducing variants and selection for short stature in Sardinia.

Nat Genet 2015 Nov 14;47(11):1352-1356. Epub 2015 Sep 14.

University of Michigan, DNA Sequencing Core, Ann Arbor, MI, USA.

We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.
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http://dx.doi.org/10.1038/ng.3403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627578PMC
November 2015

Assessing Mitochondrial DNA Variation and Copy Number in Lymphocytes of ~2,000 Sardinians Using Tailored Sequencing Analysis Tools.

PLoS Genet 2015 Jul 14;11(7):e1005306. Epub 2015 Jul 14.

Laboratory of Genetics, National Institute on Aging, NIH, Baltimore, Maryland.

DNA sequencing identifies common and rare genetic variants for association studies, but studies typically focus on variants in nuclear DNA and ignore the mitochondrial genome. In fact, analyzing variants in mitochondrial DNA (mtDNA) sequences presents special problems, which we resolve here with a general solution for the analysis of mtDNA in next-generation sequencing studies. The new program package comprises 1) an algorithm designed to identify mtDNA variants (i.e., homoplasmies and heteroplasmies), incorporating sequencing error rates at each base in a likelihood calculation and allowing allele fractions at a variant site to differ across individuals; and 2) an estimation of mtDNA copy number in a cell directly from whole-genome sequencing data. We also apply the methods to DNA sequence from lymphocytes of ~2,000 SardiNIA Project participants. As expected, mothers and offspring share all homoplasmies but a lesser proportion of heteroplasmies. Both homoplasmies and heteroplasmies show 5-fold higher transition/transversion ratios than variants in nuclear DNA. Also, heteroplasmy increases with age, though on average only ~1 heteroplasmy reaches the 4% level between ages 20 and 90. In addition, we find that mtDNA copy number averages ~110 copies/lymphocyte and is ~54% heritable, implying substantial genetic regulation of the level of mtDNA. Copy numbers also decrease modestly but significantly with age, and females on average have significantly more copies than males. The mtDNA copy numbers are significantly associated with waist circumference (p-value = 0.0031) and waist-hip ratio (p-value = 2.4×10-5), but not with body mass index, indicating an association with central fat distribution. To our knowledge, this is the largest population analysis to date of mtDNA dynamics, revealing the age-imposed increase in heteroplasmy, the relatively high heritability of copy number, and the association of copy number with metabolic traits.
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http://dx.doi.org/10.1371/journal.pgen.1005306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501845PMC
July 2015

Detection of phylogenetically informative polymorphisms in the entire euchromatic portion of human Y chromosome from a Sardinian sample.

BMC Res Notes 2015 Apr 30;8:174. Epub 2015 Apr 30.

Istituto di Ricerca Genetica e Biomedica CNR, Cagliari, Italy.

Background: Next-Generation Sequencing methods have led to a great increase in phylogenetically useful markers within the male specific portion of the Y chromosome, but previous studies have limited themselves to the study of the X-degenerate regions.

Methods: DNA was extracted from peripheral blood samples of adult males whose paternal grandfathers were born in Sardinia. The DNA samples were sequenced, genotyped and subsequently analysed for variant calling for approximately 23.1 Mbp of the Y chromosome. A phylogenetic tree was built using Network 4.6 software.

Results: From low coverage whole genome sequencing of 1,194 Sardinian males, we extracted 20,155 phylogenetically informative single nucleotide polymorphisms from the whole euchromatic region, including the X-degenerate, X-transposed, and Ampliconic regions, along with variants in other unclassified chromosome intervals and in the readable sequences of the heterochromatic region.

Conclusions: The non X-degenerate classes contain a significant portion of the phylogenetic variation of the whole chromosome and their inclusion in the analysis, almost doubling the number of informative polymorphisms, refining the known molecular phylogeny of the human Y chromosome.
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http://dx.doi.org/10.1186/s13104-015-1130-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423141PMC
April 2015