Publications by authors named "Abhishek Nag"

40 Publications

Rare variant contribution to human disease in 281,104 UK Biobank exomes.

Nature 2021 09 10;597(7877):527-532. Epub 2021 Aug 10.

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution of rare variants to common disease remains relatively unexplored. The UK Biobank contains detailed phenotypic data linked to medical records for approximately 500,000 participants, offering an unprecedented opportunity to evaluate the effect of rare variation on a broad collection of traits. Here we study the relationships between rare protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes using exome sequencing data from 269,171 UK Biobank participants of European ancestry. Gene-based collapsing analyses revealed 1,703 statistically significant gene-phenotype associations for binary traits, with a median odds ratio of 12.4. Furthermore, 83% of these associations were undetectable via single-variant association tests, emphasizing the power of gene-based collapsing analysis in the setting of high allelic heterogeneity. Gene-phenotype associations were also significantly enriched for loss-of-function-mediated traits and approved drug targets. Finally, we performed ancestry-specific and pan-ancestry collapsing analyses using exome sequencing data from 11,933 UK Biobank participants of African, East Asian or South Asian ancestry. Our results highlight a significant contribution of rare variants to common disease. Summary statistics are publicly available through an interactive portal ( http://azphewas.com/ ).
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http://dx.doi.org/10.1038/s41586-021-03855-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458098PMC
September 2021

Charge order lock-in by electron-phonon coupling in LaEuSrCuO.

Sci Adv 2021 Jun 30;7(27). Epub 2021 Jun 30.

Physik-Institut, Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.

Charge order is universal to all hole-doped cuprates. Yet, the driving interactions remain an unsolved problem. Electron-electron interaction is widely believed to be essential, whereas the role of electron-phonon interaction is unclear. We report an ultrahigh-resolution resonant inelastic x-ray scattering (RIXS) study of the in-plane bond-stretching phonon mode in stripe-ordered cuprate LaEuSrCuO Phonon softening and lifetime shortening are found around the charge ordering wave vector. In addition to these self-energy effects, the electron-phonon coupling is probed by its proportionality to the RIXS cross section. We find an enhancement of the electron-phonon coupling around the charge-stripe ordering wave vector upon cooling into the low-temperature tetragonal structure phase. These results suggest that, in addition to electronic correlations, electron-phonon coupling contributes substantially to the emergence of long-range charge-stripe order in cuprates.
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http://dx.doi.org/10.1126/sciadv.abg7394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245032PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Evolution of spin excitations from bulk to monolayer FeSe.

Nat Commun 2021 May 25;12(1):3122. Epub 2021 May 25.

Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA.

In ultrathin films of FeSe grown on SrTiO (FeSe/STO), the superconducting transition temperature T is increased by almost an order of magnitude, raising questions on the pairing mechanism. As in other superconductors, antiferromagnetic spin fluctuations have been proposed to mediate SC making it essential to study the evolution of the spin dynamics of FeSe from the bulk to the ultrathin limit. Here, we investigate the spin excitations in bulk and monolayer FeSe/STO using resonant inelastic x-ray scattering (RIXS) and quantum Monte Carlo (QMC) calculations. Despite the absence of long-range magnetic order, bulk FeSe displays dispersive magnetic excitations reminiscent of other Fe-pnictides. Conversely, the spin excitations in FeSe/STO are gapped, dispersionless, and significantly hardened relative to its bulk counterpart. By comparing our RIXS results with simulations of a bilayer Hubbard model, we connect the evolution of the spin excitations to the Fermiology of the two systems revealing a remarkable reconfiguration of spin excitations in FeSe/STO, essential to understand the role of spin fluctuations in the pairing mechanism.
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http://dx.doi.org/10.1038/s41467-021-23317-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149670PMC
May 2021

Covalency does not suppress O formation in 4d and 5d Li-rich O-redox cathodes.

Nat Commun 2021 May 20;12(1):2975. Epub 2021 May 20.

Department of Materials and Chemistry, University of Oxford, Oxford, UK.

Layered Li-rich transition metal oxides undergo O-redox, involving the oxidation of the O ions charge compensated by extraction of Li ions. Recent results have shown that for 3d transition metal oxides the oxidized O forms molecular O trapped in the bulk particles. Other forms of oxidised O such as O or (O-O) with long bonds have been proposed, based especially on work on 4 and 5d transition metal oxides, where TM-O bonding is more covalent. Here, we show, using high resolution RIXS that molecular O is formed in the bulk particles on O oxidation in the archetypal Li-rich ruthenates and iridate compounds, LiRuO, LiRuSnO and LiIrSnO. The results indicate that O-redox occurs across 3, 4, and 5d transition metal oxides, forming O, i.e. the greater covalency of the 4d and 5d compounds still favours O. RIXS and XAS data for LiIrO are consistent with a charge compensation mechanism associated primarily with Ir redox up to and beyond the 5+ oxidation state, with no evidence of O-O dimerization.
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http://dx.doi.org/10.1038/s41467-021-23154-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137948PMC
May 2021

Unraveling the Orbital Physics in a Canonical Orbital System KCuF_{3}.

Phys Rev Lett 2021 Mar;126(10):106401

Diamond Light Source, Harwell Campus, Didcot OX11 0DE, United Kingdom.

We explore the existence of the collective orbital excitations, orbitons, in the canonical orbital system KCuF_{3} using the Cu L_{3}-edge resonant inelastic x-ray scattering. We show that the nondispersive high-energy peaks result from the Cu^{2+}  dd orbital excitations. These high-energy modes display good agreement with the ab initio quantum chemistry calculation, indicating that the dd excitations are highly localized. At the same time, the low-energy excitations present clear dispersion. They match extremely well with the two-spinon continuum following the comparison with Müller ansatz calculations. The localized dd excitations and the observation of the strongly dispersive magnetic excitations suggest that the orbiton dispersion is below the resolution detection limit. Our results can reconcile with the strong local Jahn-Teller effect in KCuF_{3}, which predominantly drives orbital ordering.
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http://dx.doi.org/10.1103/PhysRevLett.126.106401DOI Listing
March 2021

Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

Commun Biol 2021 03 23;4(1):392. Epub 2021 Mar 23.

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10, odds ratio = 2.87, 95% confidence interval: 2.03-4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.
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http://dx.doi.org/10.1038/s42003-021-01910-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988141PMC
March 2021

Detection of Acoustic Plasmons in Hole-Doped Lanthanum and Bismuth Cuprate Superconductors Using Resonant Inelastic X-Ray Scattering.

Phys Rev Lett 2020 Dec;125(25):257002

Diamond Light Source, Harwell Campus, Didcot OX11 0DE, United Kingdom.

High T_{c} superconductors show a rich variety of phases associated with their charge degrees of freedom. Valence charges can give rise to charge ordering or acoustic plasmons in these layered cuprate superconductors. While charge ordering has been observed for both hole- and electron-doped cuprates, acoustic plasmons have only been found in electron-doped materials. Here, we use resonant inelastic x-ray scattering to observe the presence of acoustic plasmons in two families of hole-doped cuprate superconductors (La_{1.84}Sr_{0.16}CuO_{4} and Bi_{2}Sr_{1.6}La_{0.4}CuO_{6+δ}), crucially completing the picture. Interestingly, in contrast to the quasistatic charge ordering which manifests at both Cu and O sites, the observed acoustic plasmons are predominantly associated with the O sites, revealing a unique dichotomy in the behavior of valence charges in hole-doped cuprates.
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http://dx.doi.org/10.1103/PhysRevLett.125.257002DOI Listing
December 2020

Large-Scale Analyses Provide No Evidence for Gene-Gene Interactions Influencing Type 2 Diabetes Risk.

Diabetes 2020 11 21;69(11):2518-2522. Epub 2020 Aug 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K.

A growing number of genetic loci have been shown to influence individual predisposition to type 2 diabetes (T2D). Despite longstanding interest in understanding whether nonlinear interactions between these risk variants additionally influence T2D risk, the ability to detect significant gene-gene interaction (GGI) effects has been limited to date. To increase power to detect GGI effects, we combined recent advances in the fine-mapping of causal T2D risk variants with the increased sample size available within UK Biobank (375,736 unrelated European participants, including 16,430 with T2D). In addition to conventional single variant-based analysis, we used a complementary polygenic score-based approach, which included partitioned T2D risk scores that capture biological processes relevant to T2D pathophysiology. Nevertheless, we found no evidence in support of GGI effects influencing T2D risk. The current study was powered to detect interactions between common variants with odds ratios >1.2, so these findings place limits on the contribution of GGIs to the overall heritability of T2D.
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http://dx.doi.org/10.2337/db20-0224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576558PMC
November 2020

Coherent many-body exciton in van der Waals antiferromagnet NiPS.

Nature 2020 07 20;583(7818):785-789. Epub 2020 Jul 20.

Center for Correlated Electron Systems, Institute for Basic Science, Seoul, Republic of Korea.

An exciton is the bosonic quasiparticle of electron-hole pairs bound by the Coulomb interaction. Bose-Einstein condensation of this exciton state has long been the subject of speculation in various model systems, and examples have been found more recently in optical lattices and two-dimensional materials. Unlike these conventional excitons formed from extended Bloch states, excitonic bound states from intrinsically many-body localized states are rare. Here we show that a spin-orbit-entangled exciton state appears below the Néel temperature of 150 kelvin in NiPS, an antiferromagnetic van der Waals material. It arises intrinsically from the archetypal many-body states of the Zhang-Rice singlet, and reaches a coherent state assisted by the antiferromagnetic order. Using configuration-interaction theory, we determine the origin of the coherent excitonic excitation to be a transition from a Zhang-Rice triplet to a Zhang-Rice singlet. We combine three spectroscopic tools-resonant inelastic X-ray scattering, photoluminescence and optical absorption-to characterize the exciton and to demonstrate an extremely narrow excitonic linewidth below 50 kelvin. The discovery of the spin-orbit-entangled exciton in antiferromagnetic NiPS introduces van der Waals magnets as a platform to study coherent many-body excitons.
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http://dx.doi.org/10.1038/s41586-020-2520-5DOI Listing
July 2020

Multiorbital charge-density wave excitations and concomitant phonon anomalies in BiSrLaCuO.

Proc Natl Acad Sci U S A 2020 Jul 25;117(28):16219-16225. Epub 2020 Jun 25.

Diamond Light Source, Harwell Campus, Didcot OX11 0DE, United Kingdom;

Charge-density waves (CDWs) are ubiquitous in underdoped cuprate superconductors. As a modulation of the valence electron density, CDWs in hole-doped cuprates possess both Cu-3 and O-2 orbital character owing to the strong hybridization of these orbitals near the Fermi level. Here, we investigate underdoped BiSrLaCuO using resonant inelastic X-ray scattering (RIXS) and find that a short-range CDW exists at both Cu and O sublattices in the copper-oxide (CuO) planes with a comparable periodicity and correlation length. Furthermore, we uncover bond-stretching and bond-buckling phonon anomalies concomitant to the CDWs. Comparing to slightly overdoped BiSrLaCuO, where neither CDWs nor phonon anomalies appear, we highlight that a sharp intensity anomaly is induced in the proximity of the CDW wavevector (Q) for the bond-buckling phonon, in concert with the diffused intensity enhancement of the bond-stretching phonon at wavevectors much greater than Q Our results provide a comprehensive picture of the quasistatic CDWs, their dispersive excitations, and associated electron-phonon anomalies, which are key for understanding the competing electronic instabilities in cuprates.
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http://dx.doi.org/10.1073/pnas.2001755117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368327PMC
July 2020

Many-Body Physics of Single and Double Spin-Flip Excitations in NiO.

Phys Rev Lett 2020 Feb;124(6):067202

Diamond Light Source, Harwell Campus, Didcot OX11 0DE, United Kingdom.

Understanding many-body physics of elementary excitations has advanced our control over material properties. Here, we study spin-flip excitations in NiO using Ni L_{3}-edge resonant inelastic x-ray scattering (RIXS) and present a strikingly different resonant energy behavior between single and double spin-flip excitations. Comparing our results with single-site full-multiplet ligand field theory calculations we find that the spectral weight of the double-magnon excitations originates primarily from the double spin-flip transition of the quadrupolar RIXS process within a single magnetic site. Quadrupolar spin-flip processes are among the least studied excitations, despite being important for multiferroic or spin-nematic materials due to their difficult detection. We identify intermediate state multiplets and intra-atomic core-valence exchange interactions as the key many-body factors determining the fate of such excitations. RIXS resonant energy dependence can act as a convincing proof of existence of nondipolar higher-ranked magnetic orders in systems for which, only theoretical predictions are available.
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http://dx.doi.org/10.1103/PhysRevLett.124.067202DOI Listing
February 2020

Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels.

Hum Mol Genet 2020 03;29(5):864-875

Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.

Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites, leading to significant insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1419 subjects from the TwinsUK cohort (discovery phase), followed by replication in the Study of Health in Pomerania (SHIP-2) cohort. A total of 14 distinct locus-metabolite associations were identified in the discovery phase, most of which were replicated in SHIP-2. While only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there may be regulatory pathways of particular relevance to the salivary metabolome. In addition, some of our findings may have clinical significance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health.
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http://dx.doi.org/10.1093/hmg/ddz308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104674PMC
March 2020

Superstructure control of first-cycle voltage hysteresis in oxygen-redox cathodes.

Nature 2020 01 9;577(7791):502-508. Epub 2019 Dec 9.

Department of Materials, University of Oxford, Oxford, UK.

In conventional intercalation cathodes, alkali metal ions can move in and out of a layered material with the charge being compensated for by reversible reduction and oxidation of the transition metal ions. If the cathode material used in a lithium-ion or sodium-ion battery is alkali-rich, this can increase the battery's energy density by storing charge on the oxide and the transition metal ions, rather than on the transition metal alone. There is a high voltage associated with oxidation of O during the first charge, but this is not recovered on discharge, resulting in reduced energy density. Displacement of transition metal ions into the alkali metal layers has been proposed to explain the first-cycle voltage loss (hysteresis). By comparing two closely related intercalation cathodes, Na[LiMn]O and Na[LiMn]O, here we show that the first-cycle voltage hysteresis is determined by the superstructure in the cathode, specifically the local ordering of lithium and transition metal ions in the transition metal layers. The honeycomb superstructure of Na[LiMn]O, present in almost all oxygen-redox compounds, is lost on charging, driven in part by formation of molecular O inside the solid. The O molecules are cleaved on discharge, reforming O, but the manganese ions have migrated within the plane, changing the coordination around O and lowering the voltage on discharge. The ribbon superstructure in Na[LiMn]O inhibits manganese disorder and hence O formation, suppressing hysteresis and promoting stable electron holes on O that are revealed by X-ray absorption spectroscopy. The results show that voltage hysteresis can be avoided in oxygen-redox cathodes by forming materials with a ribbon superstructure in the transition metal layers that suppresses migration of the transition metal.
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http://dx.doi.org/10.1038/s41586-019-1854-3DOI Listing
January 2020

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Hum Genet 2018 Oct 13;137(10):847-862. Epub 2018 Oct 13.

Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR 0.48; P = 3.75 × 10), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.
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http://dx.doi.org/10.1007/s00439-018-1943-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754628PMC
October 2018

Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error.

Nat Genet 2018 06 28;50(6):834-848. Epub 2018 May 28.

Department of Population Health Sciences, Bristol Medical School, Bristol, UK.

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.
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http://dx.doi.org/10.1038/s41588-018-0127-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980758PMC
June 2018

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Nat Commun 2018 05 14;9(1):1864. Epub 2018 May 14.

Department of Ophthalmology, Flinders University, SA 5042, Adelaide, Australia.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
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http://dx.doi.org/10.1038/s41467-018-03646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951816PMC
May 2018

Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.

Nat Genet 2018 04 9;50(4):572-580. Epub 2018 Apr 9.

Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.

Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.
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http://dx.doi.org/10.1038/s41588-018-0088-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935235PMC
April 2018

Genetic African Ancestry Is Associated With Central Corneal Thickness and Intraocular Pressure in Primary Open-Angle Glaucoma.

Invest Ophthalmol Vis Sci 2017 06;58(7):3172-3180

Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands 2Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Purpose: To unravel the relationship between African ancestry, central corneal thickness (CCT), and intraocular pressure (IOP) by estimating the genetic African ancestry (GAA) proportion in primary open-angle glaucoma (POAG) patients and controls from an admixed South African Colored (SAC) and a South African Black (SAB) population.

Methods: In this case-control study, 268 POAG patients and 137 controls were recruited from a university clinic in Cape Town, South Africa. All participants were genotyped on the Illumina HumanOmniExpress beadchip or HumanOmni2.5Exome beadchip. ADMIXTURE was used to infer participant's GAA among 86,632 SNPs. Linear and logistic regression models were used to assess the relation between GAA, POAG, CCT, and IOP.

Results: The median proportion of GAA was 60% in the study population. GAA was significantly associated with thinner CCT (P < 0.001) and IOP (P = 0.034) in POAG patients. The effect of GAA on CCT was marginally different among POAG patients versus controls (P = 0.066). In POAG patients, the CCT was significantly thinner compared to controls after adjusting for age and sex (P = 0.016). In a stratified analysis in participants with >60% GAA, CCT was not associated with POAG (P = 0.550).

Conclusions: This study demonstrated that a higher proportion of GAA was associated with a thinner CCT and a higher IOP in POAG patients. Remarkably, at higher proportions of GAA, the difference in CCT between POAG and controls was reduced. This suggests that thinner CCT is not associated with POAG in Africans.
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http://dx.doi.org/10.1167/iovs.17-21716DOI Listing
June 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

Haplotype reference consortium panel: Practical implications of imputations with large reference panels.

Hum Mutat 2017 08 9;38(8):1025-1032. Epub 2017 Jun 9.

Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.

Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10 ), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers.
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http://dx.doi.org/10.1002/humu.23247DOI Listing
August 2017

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Hum Mol Genet 2017 01;26(2):438-453

Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.
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http://dx.doi.org/10.1093/hmg/ddw399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968632PMC
January 2017

Evaluation of the Myocilin Mutation Gln368Stop Demonstrates Reduced Penetrance for Glaucoma in European Populations.

Ophthalmology 2017 04 27;124(4):547-553. Epub 2016 Dec 27.

Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, United Kingdom; Department of Ophthalmology, King's College London, London, United Kingdom. Electronic address:

Purpose: Sequence variations in the myocilin (MYOC) gene account for approximately 2% to 4% of glaucoma cases. One particular MYOC mutation, Gln368Stop (dbSNP accession number: rs74315329), is the most common genetic mutation causing glaucoma by increasing intraocular pressure (IOP). The objective of this study was to evaluate the effect of this MYOC mutation on IOP using data from large-scale European population panels (directly sequenced and imputation based).

Design: Cross-sectional, cohort study.

Participants: For this study, the penetrance of the variant rs74315329 was estimated in 2 population-based cohorts, the TwinsUK (N = 6092) and the Rotterdam Study (RS) (N =11 189).

Methods: Carriers of the risk allele for rs74315329 were identified using whole-genome sequencing and imputation data (based on 1000 Genomes Project and Haplotype Reference Consortium panels). The penetrance of this variant was evaluated using IOP measurements and data on visual field testing/a diagnosis of glaucoma (if available).

Main Outcome Measures: The penetrance of the variant rs74315329 was estimated from the percentage of the carriers of the risk allele of the variant who had high IOP (ocular hypertension) or glaucoma.

Results: In our study, the observed penetrance of the variant rs74315329 in relation to increased IOP was 12.5% and 19.4% in the TwinsUK and the RS, respectively. Thus, our study suggests a much lower penetrance for rs74315329 for ocular hypertension (and thus glaucoma), in comparison with that reported previously.

Conclusions: The significance of this finding is that higher numbers of healthy individuals in the population are expected to be carriers of this mutation, which in turn reduces the utility of identifying carriers of this mutation as a screening tool for glaucoma.
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http://dx.doi.org/10.1016/j.ophtha.2016.11.018DOI Listing
April 2017

Origin of the Spin-Orbital Liquid State in a Nearly J=0 Iridate Ba_{3}ZnIr_{2}O_{9}.

Phys Rev Lett 2016 Mar 3;116(9):097205. Epub 2016 Mar 3.

Department of Materials Science, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India.

We show using detailed magnetic and thermodynamic studies and theoretical calculations that the ground state of Ba_{3}ZnIr_{2}O_{9} is a realization of a novel spin-orbital liquid state. Our results reveal that Ba_{3}ZnIr_{2}O_{9} with Ir^{5+} (5d^{4}) ions and strong spin-orbit coupling (SOC) arrives very close to the elusive J=0 state but each Ir ion still possesses a weak moment. Ab initio density functional calculations indicate that this moment is developed due to superexchange, mediated by a strong intradimer hopping mechanism. While the Ir spins within the structural Ir_{2}O_{9} dimer are expected to form a spin-orbit singlet state (SOS) with no resultant moment, substantial frustration arising from interdimer exchange interactions induce quantum fluctuations in these possible SOS states favoring a spin-orbital liquid phase down to at least 100 mK.
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http://dx.doi.org/10.1103/PhysRevLett.116.097205DOI Listing
March 2016

Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology.

Genet Epidemiol 2015 Mar 28;39(3):207-16. Epub 2015 Jan 28.

Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.

Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.
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http://dx.doi.org/10.1002/gepi.21886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480365PMC
March 2015

Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process.

Nat Commun 2014 Sep 22;5:4883. Epub 2014 Sep 22.

1] Department of Twin Research and Genetic Epidemiology, King's College London, London WC2R 2LS, UK [2] UCL Institute of Ophthalmology, London EC1V 9EL, UK.

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
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http://dx.doi.org/10.1038/ncomms5883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199103PMC
September 2014

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma.

Nat Genet 2014 Oct 31;46(10):1126-1130. Epub 2014 Aug 31.

Duke University, Duke Eye Center, Durham, NC, USA.

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.
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http://dx.doi.org/10.1038/ng.3087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177225PMC
October 2014

A genome-wide association study of intra-ocular pressure suggests a novel association in the gene FAM125B in the TwinsUK cohort.

Hum Mol Genet 2014 Jun 11;23(12):3343-8. Epub 2014 Feb 11.

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

Glaucoma is a major cause of blindness in the world. To date, common genetic variants associated with glaucoma only explain a small proportion of its heritability. We performed a genome-wide association study of intra-ocular pressure (IOP), an underlying endophenotype for glaucoma. The discovery phase of the study was carried out in the TwinsUK cohort (N = 2774) analyzing association between IOP and single nucleotide polymorphisms (SNPs) imputed to HapMap2. The results were validated in 12 independent replication cohorts of European ancestry (combined N = 22 789) that were a part of the International Glaucoma Genetics Consortium. Expression quantitative trait locus (eQTL) analyses of the significantly associated SNPs were performed using data from the Multiple Tissue Human Expression Resource (MuTHER) Study. In the TwinsUK cohort, IOP was significantly associated with a number of SNPs at 9q33.3 (P = 3.48 × 10(-8) for rs2286885, the most significantly associated SNP at this locus), within the genomic sequence of the FAM125B gene. Independent replication in a composite panel of 12 cohorts revealed consistent direction of effect and significant association (P = 0.003, for fixed-effect meta-analysis). Suggestive evidence for an eQTL effect of rs2286885 was observed for one of the probes targeting the coding region of the FAM125B gene. This gene codes for a component of a membrane complex involved in vesicular trafficking process, a function similar to that of the Caveolin genes (CAV1 and CAV2) which have previously been associated with primary open-angle glaucoma. This study suggests a novel association between SNPs in FAM125B and IOP in the TwinsUK cohort, though further studies to elucidate the functional role of this gene in glaucoma are necessary.
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http://dx.doi.org/10.1093/hmg/ddu050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030784PMC
June 2014
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