ORCID Profile
0000-0002-7464-3354
Current Organisations
IT University of Copenhagen
,
Steno Diabetes Center Copenhagen
,
Roskilde University
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Publisher: Springer Science and Business Media LLC
Date: 02-09-2200
DOI: 10.1038/S41467-019-11881-8
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration the association is replicated in 9,291 additional infants (combined P = 3.96 × 10 −14 ). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2018
Publisher: Public Library of Science (PLoS)
Date: 08-03-2017
Publisher: Springer Science and Business Media LLC
Date: 04-07-2023
DOI: 10.1038/S42003-023-04869-0
Abstract: Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis ( n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci ( ZIC1 , PRKAR1A , AZIN1/ATP6V1C1 , GLRX3 ), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.
Publisher: F1000 Research Ltd
Date: 12-01-2018
DOI: 10.12688/WELLCOMEOPENRES.12583.1
Abstract: Background: 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. Methods: 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 in iduals of European ancestry from 23 studies, and 7,721 in iduals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent in iduals. Results: We identified significant (P ·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. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU . Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
Publisher: Springer Science and Business Media LLC
Date: 30-07-2021
DOI: 10.1038/S41398-021-01480-X
Abstract: Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for s le overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG overall ) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG overall . The gene-based analysis returned three significant genes: ST3GAL3 ( P = 1.6E–06), PCDH7 ( P = 2.0E–06), and IPO13 ( P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout s le of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations ( r g ) among rater-specific assessment of AGG ranged from r g = 0.46 between self- and teacher-assessment to r g = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong r g s with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation ( r g = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2017
DOI: 10.1038/NCOMMS14977
Abstract: 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 s le. 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 the genetic susceptibility to overall adiposity and body fat distribution.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2021
DOI: 10.1038/S41467-021-26783-X
Abstract: Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1 , NOTCH4 , and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1 / KCNH8 , TRIB1 / LINC00861 , ZBTB1 , TBX21 / OSBPL7 , and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.
Publisher: Public Library of Science (PLoS)
Date: 12-10-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-09-2019
Abstract: Although studies show that diabetic kidney disease has a heritable component, searches for the genetic determinants of this complication of diabetes have had limited success. In this study, a new international genomics consortium, the JDRF funded Diabetic Nephropathy Collaborative Research Initiative, assembled nearly 20,000 s les from participants with type 1 diabetes, with and without kidney disease. The authors found 16 new diabetic kidney disease–associated loci at genome-wide significance. The strongest signal centers on a protective missense coding variant at COL4A3 , a gene that encodes a component of the glomerular basement membrane that, when mutated, causes the progressive inherited nephropathy Alport syndrome. These GWAS-identified risk loci may provide insights into the pathogenesis of diabetic kidney disease and help identify potential biologic targets for prevention and treatment. Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. Our GWAS meta-analysis included association results for up to 19,406 in iduals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain ( COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition ( BMP7) or renal biology ( COLEC11 and DDR1 ). The 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2020
DOI: 10.1101/2020.06.04.20121061
Abstract: Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium. The SNP heritability of total psychiatric problems was 5.4% (SE=0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2 , a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total psychiatric problem score were shared with known genetic variants for common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (r G 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (r G 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation of with intelligence, educational attainment, wellbeing, smoking, and body fat (r G 0.29).The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between psychiatric disorders and related traits.
Publisher: Oxford University Press (OUP)
Date: 30-01-2021
DOI: 10.1093/HMG/DDAB023
Abstract: Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) in iduals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all s les. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2019
DOI: 10.1038/S41467-018-07863-X
Abstract: Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53 , with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.
Publisher: Cold Spring Harbor Laboratory
Date: 02-11-2021
DOI: 10.1101/2021.11.01.21265592
Abstract: Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of genes important to bone biology in general, and particularly for identifying components unique to intramembranous ossification, which cannot be captured at other skeletal sites. We assessed genetic determinants of SK-BMD in 43,800 in iduals, identifying 59 genome-wide significant loci (4 novel), explaining 12.5% of its variance. Pathway and enrichment analyses of the association signals resulted in clustering within gene-sets involved in regulating the development of the skeleton overexpressed in the musculoskeletal system and enriched in enhancer and transcribed regions in osteoblasts. From the four novel loci (mapping to ZIC1, PRKAR1A, ATP6V1C1, GLRX3 ), two ( ZIC1 and PRKAR1A ) have previously been related to craniofacial developmental defects. Functional validation of skull development in zebrafish revealed abnormal cranial bone initiation that culminated in ectopic sutures and reduced BMD in mutated zic1 and atp6v1c1 fish and asymmetric bone growth and elevated BMD in mutated prkar1a fish. We confirmed a role of ZIC1 loss-of-function in suture patterning and discovered ATP6V1C1 gene associated with suture development. In light of the evidence presented suggesting that SK-BMD is genetically related to craniofacial abnormalities, our study opens new avenues to the understanding of the pathophysiology of craniofacial defects and towards the effective pharmacological treatment of bone diseases.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2018
Publisher: Springer Science and Business Media LLC
Date: 26-10-2018
DOI: 10.1038/S41467-018-06356-1
Abstract: Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 in iduals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2018
DOI: 10.1038/S41588-018-0197-6
Abstract: In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
Publisher: Wiley
Date: 05-02-2020
DOI: 10.1111/ALL.14162
Publisher: Springer Science and Business Media LLC
Date: 25-07-2017
DOI: 10.1038/S41467-017-00108-3
Abstract: Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34–52%) for TBLH-BMD, and 39% (95% CI: 30–48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29–56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4 , GALNT3 , MEPE , CPED1/WNT16 , TNFSF11 , RIN3 , and PPP6R3/LRP5 . Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.
Publisher: Cold Spring Harbor Laboratory
Date: 06-2022
DOI: 10.1101/2022.06.01.494306
Abstract: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors, although mechanisms are not well understood. Here, we performed a meta-genome-wide association study within the EAGLE consortium and investigated polygenic overlap with later-life traits, including Attention-Deficit/Hyperactivity Disorder (ADHD) and cognition. We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h 2 ), genetic correlations (r g ) and modelled underlying genetic factor structures with multivariate models. Contributions of common genetic variation to early-life vocabulary were modest (SNP-h 2 : 0.08(SE=0.01) to 0.24(SE=0.03)) and multi-factorial. Genetic overlap between infant expressive and toddler receptive vocabulary was near zero (r g =0.07(SE=0.10)), although both measures were genetically related to toddler expressive vocabulary (r g =0.69(SE=0.14) and r g =0.67(SE=0.16), respectively). Consistently, polygenic association patterns with later-life traits differed: Genetic links with cognition emerged only in toddlerhood (e.g. toddler receptive vocabulary and intelligence: r g =0.36(SE=0.12)), despite comparable study power for infant measures. Furthermore, increased polygenic ADHD risk was associated with larger infant expressive vocabulary (r g =0.23(SE=0.08)), as confirmed by ADHD-symptom-based follow-up analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC-r g =0.54(SE=0.26)). Genetic relationships with toddler receptive vocabulary were, however, opposite (ALSPAC-r g =-0.74(SE=0.23)), highlighting developmental changes in genetic architectures. Multiple genetic components contribute to early-life vocabulary development, shaping polygenic association patterns with later-life ADHD symptoms and cognition.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2023
Publisher: F1000 Research Ltd
Date: 07-08-2018
DOI: 10.12688/WELLCOMEOPENRES.12583.3
Abstract: Background: 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. Methods: 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 in iduals of European ancestry from 23 studies, and 7,721 in iduals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent in iduals. Results: We identified significant (P ·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. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU . Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
Publisher: F1000 Research Ltd
Date: 21-06-2018
DOI: 10.12688/WELLCOMEOPENRES.12583.2
Abstract: Background: 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. Methods: 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 in iduals of European ancestry from 23 studies, and 7,721 in iduals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent in iduals. Results: We identified significant (P ·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. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU . Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
Publisher: Public Library of Science (PLoS)
Date: 22-08-2022
DOI: 10.1371/JOURNAL.PONE.0273116
Abstract: Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2 , a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-09-2019
Abstract: Longitudinal data find a new variant controlling BMI in infancy and reveal genetic differences between infant and adult BMI.
Location: India
Location: Denmark
Location: Denmark
Location: Sweden
No related grants have been discovered for Tarunveer Singh Ahluwalia.