Lung function measures reflect the physiological state of the lung, and are essential to the diag... more Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression...
Chronic respiratory disorders are important contributors to the global burden of disease. Genome-... more Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation, and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less s...
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individu... more Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism…
BACKGROUND AND OBJECTIVES To facilitate and improve the diagnostic and therapeutic process by sys... more BACKGROUND AND OBJECTIVES To facilitate and improve the diagnostic and therapeutic process by systematically reviewing studies on patients with primary angiitis of the CNS (PACNS). METHODS We searched PubMed, looking at the period between 1988 and February 2020. Studies with adult patients with PACNS were included. We extracted and pooled proportions using fixed-effects models. Main outcomes were proportions of patients with certain clinical, imaging, and laboratory characteristics and neurologic outcomes. RESULTS We identified 46 cohort studies including a total of 911 patients (41% biopsy confirmed, 43% angiogram confirmed, and 16% without clear assignment to the diagnostic procedure). The most frequent onset symptoms were focal neurologic signs (63%), headache (51%), and cognitive impairment (41%). Biopsy- compared with angiogram-confirmed cases had higher occurrences of cognitive impairment (55% vs 39%) and seizures (36% vs 16%), whereas focal neurologic signs occurred less ofte...
A field experiment was conducted in a farmer’s field in Roogi village of Mudhol taluk during Khar... more A field experiment was conducted in a farmer’s field in Roogi village of Mudhol taluk during Kharif 2012. The experiment comprised of four salinity levels (ECe <2, 2-4, 4-6 and 6-8 dSm-1) and four nitrogen levels (150, 175, 200 and 225 kg N ha-1). Application of higher doses of nitrogen resulted in increased yield. The highest maize grain yield of 8.31 t ha-1 was obtained under salinity level < 2 dSm-1. Soil application of 225 kg N ha-1 recorded maximum yield (6.74 t ha-1) and it was closely followed by 200 kg N ha-1. Increased doses of N application under saline soil condition did not benefit the crop and yield remained lower. Reduced NPK uptake was recorded with the increased soil salinity. The maximum NPK uptake was observed for 225 kg ha-1 N application irrespective soil salinity level and it was closely followed by 200 kg N ha-1.
Smoking is a common risk factor for many diseases1. We conducted genome-wide association meta-ana... more Smoking is a common risk factor for many diseases1. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 × 10−8), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 × 10−69), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 × 10−12) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 × 10−8), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotin...
Skeletal tubercular infections that do not involve the spine or large joints are rarely encounter... more Skeletal tubercular infections that do not involve the spine or large joints are rarely encountered. This case series aims to highlight the importance of imaging in diagnosing skeletal tuberculosis (TB) at uncommon sites in clinically unsuspected patients by demonstrating specific imaging findings. We present the clinical details and imaging findings of seven pathologically confirmed cases of extraspinal skeletal TB. A multimodality imaging approach including radiography, ultrasonography (USG) and computed tomography (CT) scan was used in most cases. The imaging studies revealed an infective soft tissue collection over different sites including the sternoclavicular joint, acromion process, chest wall and temporo-mandibular joint, along with destruction and erosion of the underlying or adjacent bones. In tubercular endemic countries, strong clinical suspicion should be entertained in cases presenting with a soft tissue collection, even around unusual skeletal sites.
Major depression is a debilitating psychiatric illness that is typically associated with low mood... more Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes asso...
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple scle... more The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative ap...
Over 90 regions of the genome have been associated with lung function to date, many of which have... more Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease (COPD). We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1 /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2.8x10 -7 ) associations with six SNPs: a nonsynonymous variant in RPAP1 , which is predicted to be damaging, three intronic SNPs ( SEC24C , CASC17 and UQCC1 ) and two intergenic SNPs near to LY86 and FGF10 . eQTL analyses found evidence for regulation of gene expression at three signals and implicated several genes including TYRO3 an...
Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity... more Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute t...
Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, pot... more Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter th...
Lung function measures reflect the physiological state of the lung, and are essential to the diag... more Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression...
Chronic respiratory disorders are important contributors to the global burden of disease. Genome-... more Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation, and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less s...
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individu... more Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism…
BACKGROUND AND OBJECTIVES To facilitate and improve the diagnostic and therapeutic process by sys... more BACKGROUND AND OBJECTIVES To facilitate and improve the diagnostic and therapeutic process by systematically reviewing studies on patients with primary angiitis of the CNS (PACNS). METHODS We searched PubMed, looking at the period between 1988 and February 2020. Studies with adult patients with PACNS were included. We extracted and pooled proportions using fixed-effects models. Main outcomes were proportions of patients with certain clinical, imaging, and laboratory characteristics and neurologic outcomes. RESULTS We identified 46 cohort studies including a total of 911 patients (41% biopsy confirmed, 43% angiogram confirmed, and 16% without clear assignment to the diagnostic procedure). The most frequent onset symptoms were focal neurologic signs (63%), headache (51%), and cognitive impairment (41%). Biopsy- compared with angiogram-confirmed cases had higher occurrences of cognitive impairment (55% vs 39%) and seizures (36% vs 16%), whereas focal neurologic signs occurred less ofte...
A field experiment was conducted in a farmer’s field in Roogi village of Mudhol taluk during Khar... more A field experiment was conducted in a farmer’s field in Roogi village of Mudhol taluk during Kharif 2012. The experiment comprised of four salinity levels (ECe <2, 2-4, 4-6 and 6-8 dSm-1) and four nitrogen levels (150, 175, 200 and 225 kg N ha-1). Application of higher doses of nitrogen resulted in increased yield. The highest maize grain yield of 8.31 t ha-1 was obtained under salinity level < 2 dSm-1. Soil application of 225 kg N ha-1 recorded maximum yield (6.74 t ha-1) and it was closely followed by 200 kg N ha-1. Increased doses of N application under saline soil condition did not benefit the crop and yield remained lower. Reduced NPK uptake was recorded with the increased soil salinity. The maximum NPK uptake was observed for 225 kg ha-1 N application irrespective soil salinity level and it was closely followed by 200 kg N ha-1.
Smoking is a common risk factor for many diseases1. We conducted genome-wide association meta-ana... more Smoking is a common risk factor for many diseases1. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 × 10−8), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 × 10−69), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 × 10−12) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 × 10−8), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotin...
Skeletal tubercular infections that do not involve the spine or large joints are rarely encounter... more Skeletal tubercular infections that do not involve the spine or large joints are rarely encountered. This case series aims to highlight the importance of imaging in diagnosing skeletal tuberculosis (TB) at uncommon sites in clinically unsuspected patients by demonstrating specific imaging findings. We present the clinical details and imaging findings of seven pathologically confirmed cases of extraspinal skeletal TB. A multimodality imaging approach including radiography, ultrasonography (USG) and computed tomography (CT) scan was used in most cases. The imaging studies revealed an infective soft tissue collection over different sites including the sternoclavicular joint, acromion process, chest wall and temporo-mandibular joint, along with destruction and erosion of the underlying or adjacent bones. In tubercular endemic countries, strong clinical suspicion should be entertained in cases presenting with a soft tissue collection, even around unusual skeletal sites.
Major depression is a debilitating psychiatric illness that is typically associated with low mood... more Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes asso...
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple scle... more The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative ap...
Over 90 regions of the genome have been associated with lung function to date, many of which have... more Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease (COPD). We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1 /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2.8x10 -7 ) associations with six SNPs: a nonsynonymous variant in RPAP1 , which is predicted to be damaging, three intronic SNPs ( SEC24C , CASC17 and UQCC1 ) and two intergenic SNPs near to LY86 and FGF10 . eQTL analyses found evidence for regulation of gene expression at three signals and implicated several genes including TYRO3 an...
Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity... more Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute t...
Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, pot... more Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter th...
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