Publications by authors named "Aniket Mishra"

35 Publications

Genomic studies across the lifespan point to early mechanisms determining subcortical volumes.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Oct 23. Epub 2021 Oct 23.

University of Bordeaux, INSERM, Bordeaux Population Health Center, UMR1219, F-33000 Bordeaux, France; Bordeaux University Hospital, Department of Neurology, Institute of Neurodegenerative Diseases, F-33000 Bordeaux, France. Electronic address:

Background: Subcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration.

Methods: Using large population-based brain imaging datasets across the lifespan (N<40,628) we aimed to: (i) estimate the heritability of subcortical volumes in young (18-35), middle (35-65), and older age (65+), and their genetic correlation across age groups; (ii) identify whether genetic loci associated with subcortical volumes in older persons also show associations in early adulthood, and explore underlying genes using transcriptome-wide association studies; (iii) explore their association with neurological phenotypes.

Results: Heritability of subcortical volumes consistently decreased with increasing age. Genetic risk scores for smaller caudate nucleus, putamen and hippocampus volume in older adults were associated with smaller volumes in young adults. Individually, ten loci associated with subcortical volumes in older adults also showed associations in young adults. Within these loci, transcriptome-wide association studies showed that expression of several genes in brain tissues (especially MYLK2 and TUFM) was associated with subcortical volumes in both age-groups. One risk variant for smaller caudate nucleus volume (TUFM locus) was associated with lower cognitive performance. Genetically-predicted Alzheimer's disease was associated with smaller subcortical volumes in middle and older age.

Conclusions: Our findings provide novel insights into the genetic determinants of subcortical volumes across the lifespan. More studies are needed to decipher the underlying biology and clinical impact.
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http://dx.doi.org/10.1016/j.bpsc.2021.10.011DOI Listing
October 2021

Copper-Catalyzed Direct sp C-H Silylation of Arylamides Using Disilanes.

Org Lett 2021 Jun 13;23(12):4521-4526. Epub 2021 May 13.

Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India.

A copper-catalyzed method for direct intermolecular -silylation of benzamides has been developed that affords organosilane products in moderate to high yields. The key features include: (i) use of commercially available disilanes as a silicon source with 8-aminoquinoline as a bidentate directing group, (ii) use of earth-abundant first-row transition metal, (iii) operationally simple conditions without the need of an inert atmosphere, and (iv) tolerance of a wide range of functional groups. The practicality and effectiveness of this method have been demonstrated by a gram-scale experiment. This strategy, therefore, constitutes a convenient way of constructing C-Si bonds useful for synthetic organic chemistry.
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http://dx.doi.org/10.1021/acs.orglett.1c01129DOI Listing
June 2021

Straightforward Access to Anthrone Functionalized Benzylic Amines via Organocatalytic 1,2-Addition of Anthrones to Imines at Ambient Temperature.

J Org Chem 2021 Mar 23;86(5):4131-4142. Epub 2021 Feb 23.

Organic and Medicinal Chemistry Division, CSIR - Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India.

Activation of anthrone via benzylic deprotonation in the presence of triethylamine paves the way for the 1,2-addition reaction with imines to provide the desired functionalized anthrones in good to excellent yields under mild and operationally simple reaction conditions with a broad range of substrate scopes without using any external additives or toxic stoichiometric reagents.
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http://dx.doi.org/10.1021/acs.joc.0c02959DOI Listing
March 2021

Awareness about breast cancer in first-year junior residents at a tertiary care institute in India: A cross-sectional study.

Med J Armed Forces India 2021 Feb 2;77(Suppl 1):S208-S214. Epub 2021 Feb 2.

Assistant Professor (General Surgery), PGIMER, Chandigarh, India.

Background: Primary physicians have a very important role in identifying early breast cancer, as well as promotion of awareness about breast cancer to general public. However, there is insufficient data about the knowledge of doctors, who have just finished their basic medical training, on breast cancer.

Methods: All the postgraduate residents who had joined within the last 3 months, irrespective of the department, were invited to take part in the study. After explaining the aims of the study telephonically, consent was taken through online signatures and the participants were asked to fill online proformas. Descriptive statistics were used, and chi-square test was used to compare groups. value of less than 0.05 was considered as significant.

Results: A total of 106 participants took part in the study. Only 63 (59.4%) participants had satisfactory knowledge about the warning signs of breast cancer. Apart from question of ideal frequency of breast examination, which was answered by 59 (55.7%) participants, the rest of the questions were answered correctly by less than 50% of participants. On the questions on risk factors, 102 (96.5%) of the participants were assessed to have adequate knowledge. Overall only 51 (48.1%) participants were assessed to have satisfactory knowledge about warning signs, screening and risk factors related to breast cancer.

Conclusions: The awareness about warning signs, risk factors and screening practices of breast cancer in newly joined residents was less than satisfactory. To improve this level of awareness, significant steps are needed at the level of undergraduate teaching.
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http://dx.doi.org/10.1016/j.mjafi.2020.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873697PMC
February 2021

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

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

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Iridium-catalyzed direct C-H arylation of cyclic -sulfonyl ketimines with arylsiloxanes at ambient temperature.

Org Biomol Chem 2020 Sep;18(36):7074-7078

Organic & Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India.

An iridium-catalyzed ortho-selective C-H arylation of cyclic N-sulfonyl ketimines has been achieved with environmentally benign aryl siloxanes. The reaction is highly efficient and proceeds at ambient temperature which is the key feature of the methodology considering the weak coordination nature of the substrate as well as the sluggish reactivity of siloxanes. A wide array of pharmaceutically relevant novel biaryls has been synthesized under operationally simple conditions.
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http://dx.doi.org/10.1039/d0ob01212bDOI Listing
September 2020

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.

Cereb Cortex 2020 06;30(7):4121-4139

Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04109 Leipzig, Germany.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.
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http://dx.doi.org/10.1093/cercor/bhaa035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947185PMC
June 2020

Diastereoselective Spirocyclization of Benzoxazines with Nitroalkenes via Rhodium-Catalyzed C-H Functionalization/Annulation Cascade under Mild Conditions.

Org Lett 2020 Feb 30;22(4):1340-1344. Epub 2020 Jan 30.

Organic and Medicinal Chemistry Division , CSIR-Indian Institute of Chemical Biology , 4-Raja S. C. Mullick Road , Jadavpur, Kolkata 700032 , India.

A Rh(III)-catalyzed [3 + 2] annulation of benzoxazines with nitroolefins that proceeds via redox-neutral C-H functionalization has been demonstrated, leading to the novel class of spirocycles in a single step. The construction of three continuous stereogenic centers has been achieved starting from easily accessible achiral substrates in an atom-efficient manner under mild reaction conditions. A broad range of pharmaceutically relevant nitro substituted spirocyclic 2,3-dihydro-1,4-benzoxazine derivatives has been synthesized in good to excellent yields with high diastereoselectivity.
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http://dx.doi.org/10.1021/acs.orglett.9b04652DOI Listing
February 2020

Corticosteroids and Regional Variations in Thickness of the Human Cerebral Cortex across the Lifespan.

Cereb Cortex 2020 03;30(2):575-586

Bordeaux Population Health Research Center, INSERM UMR, University of Bordeaux, Bordeaux 33076, France.

Exposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4-97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life.
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http://dx.doi.org/10.1093/cercor/bhz108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444740PMC
March 2020

Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.

Brain 2019 04;142(4):1009-1023

The University of Texas Health Science Center at Houston, Houston, TX, USA.

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.
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http://dx.doi.org/10.1093/brain/awz024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439324PMC
April 2019

Diastereoselective Spirocyclization of Cyclic N-Sulfonyl Ketimines with Nitroalkenes via Iridium-Catalyzed Redox-Neutral Cascade Reaction.

Org Lett 2019 04 21;21(7):2056-2059. Epub 2019 Feb 21.

Organic and Medicinal Chemistry Division , CSIR-Indian Institute of Chemical Biology , 4-Raja S. C. Mullick Road , Jadavpur, Kolkata 700032 , India.

An Ir(III)-catalyzed [3 + 2] annulation of weakly coordinating N-sulfonyl ketimines with challenging α, β-unsaturated nitro olefins has been achieved via redox-neutral C-H functionalization in the presence of a catalytic amount of silver hexafluoroantimonate. The generation of three consecutive stereogenic centers in a single step via direct C-H functionalization is the prime feature of this methodology. A wide array of pharmaceutically relevant nitro-substituted spirocyclic benzosultams was synthesized with good to excellent diastereoselectivity as well as in high yield starting from easily accessible substrates.
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http://dx.doi.org/10.1021/acs.orglett.9b00295DOI Listing
April 2019

Serum 25-Hydroxyvitamin D Concentrations and Ischemic Stroke and Its Subtypes.

Stroke 2018 10;49(10):2508-2511

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (M.T., H.S.M.).

Background and Purpose- Observational studies have reported increased risk of ischemic stroke among individuals with low serum 25-hydroxyvitamin D (S-25OHD) concentrations but uncertainty remains about the causality of this association. We sought to determine whether S-25OHD concentrations are causally associated with ischemic stroke and its subtypes using Mendelian randomization. Methods- We used summary-level data for ischemic stroke (34 217 cases and 404 630 noncases) from the MEGASTROKE consortium. As instruments, we used 6 single nucleotide polymorphisms, explaining 7.5% of the variance in S-25OHD, previously identified to be associated with S-25OHD concentrations in the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits consortium (n=79 366). The analyses were conducted using the inverse-variance-weighted method and complemented with the weighted median, heterogeneity-penalized, and Mendelian randomization-Egger approaches. Results- Genetically higher S-25OHD concentration was not associated with ischemic stroke. The odds ratios (95% CI) per genetically predicted 1-SD (≈18 nmol/L) increase in S-25OHD concentrations, based on all 6 single nucleotide polymorphisms, were 1.01 (0.94-1.08; P=0.84) for all ischemic stroke, 0.94 (0.80-1.11; P=0.49) for large artery stroke, 0.95 (0.82-1.11; P=0.55) for small vessel stroke, and 1.02 (0.90-1.16; P=0.74) for cardioembolic stroke. The results were similar in sensitivity analyses. Conclusions- These findings provide no support that higher S-25OHD concentrations are causally associated with any ischemic stroke subtype. Thus, vitamin D supplementation will unlikely reduce the risk of ischemic stroke in the general population.
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http://dx.doi.org/10.1161/STROKEAHA.118.022242DOI Listing
October 2018

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

Stroke 2018 08;49(8):1812-1819

Department of Biochemistry (D.W.B., N.D.P.), Wake Forest School of Medicine, Winston-Salem, NC.

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P=4.5×10) partially independent of known common signal ( P=1.4×10). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; P=1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P=2.8×10). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
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http://dx.doi.org/10.1161/STROKEAHA.118.020689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202149PMC
August 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

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Nat Genet 2018 04 12;50(4):524-537. Epub 2018 Mar 12.

Institute of Cardiovascular Research, Royal Holloway University of London, London, UK, and Ashford and St Peters Hospital, Surrey, UK.

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
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http://dx.doi.org/10.1038/s41588-018-0058-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968830PMC
April 2018

Ir(III)/MPAA-Catalyzed Mild and Selective C-H Amidation of N-Sulfonyl Ketimines: Access To Benzosultam-Fused Quinazolines/Quinazolinones.

J Org Chem 2018 04 9;83(7):3756-3767. Epub 2018 Mar 9.

Organic and Medicinal Chemistry Division , Indian Institute of Chemical Biology , 4-Raja S. C. Mullick Road , Jadavpur , Kolkata 700032 , India.

Ir(III)-catalyzed unprecedented mild C-H amidation for weakly coordinating cyclic N-sulfonyl ketimines, accelerated by a mono protected l-amino acid, has been developed. The method uses 1,4,2-dioxazol-5-ones as the robust amidating reagent in conjunction with a catalytic amount of silver triflate. It is highly selective and does not require a stoichiometric amount of oxidants or additives. A series of mechanistic experiments was performed to gain some insights into the reaction mechanism. The strategy provides easy access to novel benzosultam-quinazoline and benzosultam-quinazolinone hybrid scaffolds endowed with pharmaceutically relevant features.
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http://dx.doi.org/10.1021/acs.joc.8b00125DOI Listing
April 2018

Rhodium-Catalyzed sp C-H Acetoxylation of N-Aryl Azaindoles/N-Heteroaryl Indolines.

J Org Chem 2017 12 7;82(23):12406-12415. Epub 2017 Nov 7.

Organic and Medicinal Chemistry Division, Indian Institute of Chemical Biology , 4-Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India.

A silver- and copper-free rhodium-catalyzed C-H acetoxylation reaction of azaindoles has been achieved at near ambient temperature employing PIDA as a nonmetallic acetoxy source. The method is highly selective, efficient, and scalable and requires acetic anhydride as the sole additive. The scope of the reaction has been successfully tested with a wide array of medicinally important heterocyclic scaffolds with diverse functional group tolerance. A series of kinetic experiments was conducted to gain detailed insight into the reaction mechanism. The methodology developed could be successfully expanded for C7-acetoxylation of indoline derivatives using pyrimidine as a detachable directing group for the synthesis of 7-hydroxyindole.
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http://dx.doi.org/10.1021/acs.joc.7b02203DOI Listing
December 2017

Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia.

Brain 2017 05;140(5):1437-1446

Department of Complex Trait Genetics, VU University, Center for Neurogenomics and Cognitive Research, Amsterdam, 1081 HV, The Netherlands.

Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.
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http://dx.doi.org/10.1093/brain/awx066DOI Listing
May 2017

A Novel Approach for Pathway Analysis of GWAS Data Highlights Role of BMP Signaling and Muscle Cell Differentiation in Colorectal Cancer Susceptibility - Erratum.

Twin Res Hum Genet 2017 04 23;20(2):186. Epub 2017 Feb 23.

Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colorectal Cancer Family Registry (CCFR), andStatistical Genetics,QIMR Berghofer Medical Research Institute,Brisbane,Queensland,Australia.

The publishers regret to announce that the affiliation for the above paper was incorrectly inserted. The correct affiliation is below: Aniket Mishra1, Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colorectal Cancer Family Registry (CCFR), and Stuart MacGregor1 1 Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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http://dx.doi.org/10.1017/thg.2017.6DOI Listing
April 2017

A Novel Approach for Pathway Analysis of GWAS Data Highlights Role of BMP Signaling and Muscle Cell Differentiation in Colorectal Cancer Susceptibility.

Twin Res Hum Genet 2017 02;20(1):1-9

Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colorectal Cancer Family Registry (CCFR),and Statistical Genetics,QIMR Berghofer Medical Research Institute,Brisbane,Queensland,Australia.

Genome-wide association studies (GWAS) have revolutionized the field of gene mapping. As the GWAS field matures, it is becoming clear that for many complex traits, a proportion of the missing heritability is attributable to common variants of individually small effect. Detecting these small effects individually can be difficult, and statistical power would be increased if relevant variants could be grouped together for testing. Here, we propose a VEGAS2Pathway approach that aggregates association strength of individual markers into pre-specified biological pathways. It accounts for gene size and linkage disequilibrium between markers using simulations from the multivariate normal distribution. Pathway size is taken into account via a resampling approach. Importantly, since the approach only requires summary data, the method can easily be applied in all GWASs, including meta-analysis, singleton-based, family-based, and DNA-pooling-based designs. This approach is implemented in a user-friendly web page https://vegas2.qimrberghofer.edu.au and a command line tool. The web implementation uses gene-sets from the gene ontology (GO), curated gene-sets from MSigDB (containing canonical pathways and gene-sets from BIOCARTA, REACTOME, KEGG databases), PANTHER, and pathway commons databases, enabling analysis of a wide range of complex traits. We applied this method on a colorectal cancer GWAS meta-analysis data set (10,934 cases, 12,328 controls) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). We report statistically significant enrichment of association signal for the 'BMP signaling' and 'muscle cell differentiation' pathways, suggesting a possible role for these pathways onto the risk of colorectal cancer.
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http://dx.doi.org/10.1017/thg.2016.100DOI Listing
February 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

Ruthenium-Catalyzed Direct and Selective C-H Cyanation of N-(Hetero)aryl-7-azaindoles.

J Org Chem 2016 08 22;81(15):6525-34. Epub 2016 Jul 22.

Organic and Medicinal Chemistry Division, Indian Institute of Chemical Biology , 4-Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India.

An efficient, highly regioselective, and scalable ruthenium-catalyzed o-aryl C-H mono-cyanation of N-aryl-7-azaindoles to form N-(2-cyanoaryl)-7-azaindoles has been developed through N-directed ortho C-H activation using N-cyano-N-phenyl-p-toluenesulfonamide as cyanating reagent in the presence of AgOTf and NaOAc in DCE. A range of substrates has furnished cyanated azaindoles in good to excellent yields under the simple reaction conditions. Involvement of C-H metalation has been supported by a kinetic study. This methodology provides easy access to a class of pharmaceutically significant molecules and their precursors.
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http://dx.doi.org/10.1021/acs.joc.6b01148DOI Listing
August 2016

Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett's esophagus.

Hum Mol Genet 2016 Feb 23;25(4):828-35. Epub 2015 Dec 23.

Statistical Genetics Laboratory.

Esophageal adenocarcinoma (EA) is a rapidly fatal cancer with rising incidence in the developed world. Most EAs arise in a metaplastic epithelium, Barrett's esophagus (BE), which is associated with greatly increased risk of EA. One of the key risk factors for both BE and EA is chronic gastroesophageal reflux disease (GERD). This study used the linkage disequilibrium (LD) score regression and genomic profile risk scoring approaches to investigate the contribution of multiple common single-nucleotide polymorphisms (SNPs) to the risk of GERD, and the extent of genetic overlap between GERD and BE or EA. Using LD score regression, we estimated an overall phenotypic variance of 7% (95% CI 3-11%) for GERD explained by all the genotyped SNPs. A genetic correlation of 77% (s.e. = 24%, P = 0.0012) between GERD and BE and 88% between GERD and EA (s.e. = 25%, P = 0.0004) was estimated using the LD score regression approach. Results from the genomic profile risk scoring approach, as a robustness check, were broadly similar to those from the LD score regression. This study provides the first evidence for a polygenic basis for GERD and supports for a polygenic overlap between GERD and BE, and GERD and EA.
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http://dx.doi.org/10.1093/hmg/ddv512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743691PMC
February 2016

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure.

Hum Mol Genet 2015 May 30;24(9):2689-99. Epub 2015 Jan 30.

Statistical and

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (β = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8)], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.
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http://dx.doi.org/10.1093/hmg/ddv027DOI Listing
May 2015

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

VEGAS2: Software for More Flexible Gene-Based Testing.

Twin Res Hum Genet 2015 Feb 18;18(1):86-91. Epub 2014 Dec 18.

Statistical Genetics Group,QIMR Berghofer Medical Research Institute,Brisbane,Queensland,Australia.

Gene-based tests such as versatile gene-based association study (VEGAS) are commonly used following per-single nucleotide polymorphism (SNP) GWAS (genome-wide association studies) analysis. Two limitations of VEGAS were that the HapMap2 reference set was used to model the correlation between SNPs and only autosomal genes were considered. HapMap2 has now been superseded by the 1,000 Genomes reference set, and whereas early GWASs frequently ignored the X chromosome, it is now commonly included. Here we have developed VEGAS2, an extension that uses 1,000 Genomes data to model SNP correlations across the autosomes and chromosome X. VEGAS2 allows greater flexibility when defining gene boundaries. VEGAS2 offers both a user-friendly, web-based front end and a command line Linux version. The online version of VEGAS2 can be accessed through https://vegas2.qimrberghofer.edu.au/. The command line version can be downloaded from https://vegas2.qimrberghofer.edu.au/zVEGAS2offline.tgz. The command line version is developed in Perl, R and shell scripting languages; source code is available for further development.
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http://dx.doi.org/10.1017/thg.2014.79DOI Listing
February 2015

Copper(I)-promoted cycloalkylation-peroxidation of unactivated alkenes via sp(3) C-H functionalisation.

Org Biomol Chem 2015 Feb;13(5):1307-12

Department of Chemistry, Indian Institute of Technology Guwahati, 781 039, Assam, India.

A copper(I)-promoted cycloalkylation-peroxidation strategy has been developed via a three-component reaction involving cycloalkanes, tert-butyl hydroperoxide (TBHP) and internal conjugated alkenes possessing electron-withdrawing groups (EWGs). This process installs C-O and C-C bonds via sp(3) C-H functionalisation with concomitant generation of two stereocentres. This regioselective radical addition of coumarin system is opposite to that of styrene.
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http://dx.doi.org/10.1039/c4ob01962hDOI Listing
February 2015
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