ORCID Profile
0000-0001-8520-8860
Current Organisation
Umeå University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2021
DOI: 10.1186/S13073-021-00917-8
Abstract: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. The study s le was comprised of 7988 in iduals of erse ancestry. Common-variant and pathway analyses included an additional 13,257 in iduals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. We identified a multi-ethnic set-based rare-variant association ( p = 3.48 × 10 −8 ) on chromosome X with ARMCX3 . Additional rare-variant associations include ARMCX3-AS1 , MRPS33 , and C16orf90 . Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A -mediated hypoxic response.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2017
DOI: 10.1038/NCOMMS16140
Abstract: Nature Communications 8: Article number: 15805 (2017) Published: 14 June 2017 Updated: 2 August 2017 In Supplementary Fig. 10 of this Article, images for panels a and b were inadvertently omitted. The correct version of Supplementary Fig. 10 is provided as Supplementary Information associated withthis Erratum.
Publisher: Elsevier BV
Date: 12-2022
Publisher: Springer Science and Business Media LLC
Date: 25-09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 03-06-2019
DOI: 10.1101/652966
Abstract: Sleep-disordered breathing (SDB) is a common disorder associated with significant morbidity. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program we report the first whole-genome sequence analysis of SDB. We identified 4 rare gene-based associations with SDB traits in 7,988 in iduals of erse ancestry and 4 replicated common variant associations with inclusion of additional s les (n=13,257). We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10 −8 ) on chromosome X with ARMCX3 . Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Results highlighted associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis and HIF1A -mediated hypoxic response.
Publisher: Cold Spring Harbor Laboratory
Date: 30-03-2021
DOI: 10.1101/2021.03.29.437546
Abstract: Cells rapidly lose their physiological phenotype upon disruption of their extracellular matrix (ECM)-intracellular cytoskeleton interactions. Here, we investigated acute effects of ECM disruption on cellular and mitochondrial morphology, transcriptomic signatures, and Ca 2+ handling in adult mouse skeletal muscle fibers. Adult skeletal muscle fibers were isolated from mouse toe muscle either by collagenase-induced dissociation of the ECM or by mechanical dissection that leaves the contiguous ECM intact. Experiments were generally performed four hours after cell isolation. At this time, there were striking differences in the gene expression patterns between fibers isolated with the two methods 24h after cell isolation, enzymatically dissociated fibers had transcriptomic signatures resembling dystrophic phenotypes. Mitochondrial appearance was grossly similar in the two groups, but 3D electron microscopy revealed shorter and less branched mitochondria in enzymatically dissociated than in mechanically dissected fibers. Similar increases in free cytosolic [Ca 2+ ] during repeated tetanic stimulation were accompanied by marked mitochondrial Ca 2+ uptake only in enzymatically dissociated muscle fibers. The aberrant mitochondrial Ca 2+ uptake was partially prevented by the mitochondrial Ca 2+ uniporter inhibitor Ru360 and by cyclosporine A and NV556, which inhibit the mitochondrial protein Ppif (also called cyclophilin D). Importantly, inhibition of Ppif with NV556 significantly improved survival of mice with mitochondrial myopathy in which muscle mitochondria take up excessive amounts of Ca 2+ even with an intact ECM. In conclusion, skeletal muscle fibers isolated by collagenase-induced dissociation of the ECM display aberrant mitochondrial Ca 2+ uptake, which involves a Ppif-dependent mitochondrial Ca 2+ influx resembling that observed in mitochondrial myopathies.
Publisher: Oxford University Press (OUP)
Date: 09-10-2020
Abstract: Poor sleep quality can have harmful health consequences. Although many aspects of sleep are heritable, the understandings of genetic factors involved in its physiology remain limited. Here, we performed a genome-wide association study (GWAS) using the Pittsburgh Sleep Quality Index (PSQI) in a multi-ethnic discovery cohort (n = 2868) and found two novel genome-wide loci on chromosomes 2 and 7 associated with global sleep quality. A meta-analysis in 12 independent cohorts (100 000 in iduals) replicated the association on chromosome 7 between NPY and MPP6. While NPY is an important sleep gene, we tested for an independent functional role of MPP6. Expression data showed an association of this locus with both NPY and MPP6 mRNA levels in brain tissues. Moreover, knockdown of an orthologue of MPP6 in Drosophila melanogaster sleep center neurons resulted in decreased sleep duration. With convergent evidence, we describe a new locus impacting human variability in sleep quality through known NPY and novel MPP6 sleep genes.
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
Publisher: Springer Science and Business Media LLC
Date: 14-06-2017
DOI: 10.1038/NCOMMS15805
Abstract: Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 in iduals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755 ), expression quantitative trait loci (eQTLs) (influencing GNG11 , RGS6 and NEO1 ), or are located in genes preferentially expressed in the sinoatrial node ( GNG11 , RGS6 and HCN4) . Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74 r g −0.55) and blood pressure (−0.35 r g −0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants ( GNG11 , RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.
Publisher: Cold Spring Harbor Laboratory
Date: 21-07-2022
DOI: 10.1101/2022.07.20.500802
Abstract: Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in s les of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 studies with 88,316 MD cases and 902,757 controls to previously reported data from in iduals of European ancestry. This includes s les of African (36% of effective s le size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latinx participants (32%). The multi-ancestry GWAS identified 190 significantly associated loci, 53 of them novel. For previously reported loci from GWAS in European ancestry the power-adjusted transferability ratio was 0.6 in the Hispanic/Latinx group and 0.3 in each of the other groups. Fine-mapping benefited from additional s le ersity: the number of credible sets with ≤5 variants increased from 3 to 12. A transcriptome-wide association study identified 354 significantly associated genes, 205 of them novel. Mendelian Randomisation showed a bidirectional relationship with BMI exclusively in s les of European ancestry. This first multi-ancestry GWAS of MD demonstrates the importance of large erse s les for the identification of target genes and putative mechanisms.
Publisher: American Thoracic Society
Date: 15-11-2022
Publisher: Public Library of Science (PLoS)
Date: 27-12-2022
DOI: 10.1371/JOURNAL.PGEN.1010557
Abstract: Genetic association studies of many heritable traits resulting from physiological testing often have modest s le sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations in underpowered validation cohorts and leads to higher interpretability. Here, as an exemplar, we use Obstructive Sleep Apnea (OSA), a common disorder diagnosed using overnight multi-channel physiological testing. We leverage pleiotropy with relevant cellular and cardio-metabolic phenotypes and gene expression traits to map new risk loci in an underpowered OSA GWAS. We identify several pleiotropic loci harboring suggestive associations to OSA and genome-wide significant associations to other traits, and show that their OSA association replicates in independent cohorts of erse ancestries. By investigating pleiotropic loci, our strategy allows proposing new hypotheses about OSA pathobiology across many physiological layers. For ex le, we identify and replicate the pleiotropy across the plateletcrit, OSA and an eQTL of DNA primase subunit 1 ( PRIM1 ) in immune cells. We find suggestive links between OSA, a measure of lung function (FEV 1 /FVC), and an eQTL of matrix metallopeptidase 15 ( MMP15 ) in lung tissue. We also link a previously known genome-wide significant peak for OSA in the hexokinase 1 ( HK1) locus to hematocrit and other red blood cell related traits. Thus, the analysis of pleiotropic associations has the potential to assemble erse phenotypes into a chain of mechanistic hypotheses that provide insight into the pathogenesis of complex human diseases.
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2022
DOI: 10.1101/2022.05.11.22274314
Abstract: Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. In idual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Publisher: American Thoracic Society
Date: 15-06-2021
Publisher: Cold Spring Harbor Laboratory
Date: 05-10-2017
DOI: 10.1101/196048
Abstract: Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 in iduals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.
Publisher: Elsevier BV
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 03-2023
DOI: 10.1038/S41588-023-01314-0
Abstract: Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. In idual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2019
Publisher: Springer Science and Business Media LLC
Date: 15-04-2021
Publisher: Springer Science and Business Media LLC
Date: 30-07-2018
DOI: 10.1038/S41467-018-05369-0
Abstract: Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 in iduals of European ( N = 60,552), African ( N = 8429), Asian ( N = 9959), and Hispanic/Latino ( N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12 . Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
Publisher: Public Library of Science (PLoS)
Date: 16-04-2019
Publisher: Proceedings of the National Academy of Sciences
Date: 21-01-2020
Abstract: De novo mutations (DNMs), or mutations that appear in an in idual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of erse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed s les. Genome-wide heterozygosity does correlate with DNM rate, but only explains % of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between in iduals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed in iduals. However, we did find significantly fewer DNMs in Amish in iduals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability ( h 2 ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2021
DOI: 10.1038/S41366-021-00817-2
Abstract: Neck circumference, an index of upper airway fat, has been suggested to be an important measure of body-fat distribution with unique associations with health outcomes such as obstructive sleep apnea and metabolic disease. This study aims to study the genetic bases of neck circumference. We conducted a multi-ethnic genome-wide association study of neck circumference, adjusted and unadjusted for BMI, in up to 15,090 European Ancestry (EA) and African American (AA) in iduals. Because sexually dimorphic associations have been observed for anthropometric traits, we conducted both sex-combined and sex-specific analysis. We identified rs227724 near the Noggin ( NOG) gene as a possible quantitative locus for neck circumference in men ( N = 8831, P = 1.74 × 10 −9 ) but not in women ( P = 0.08). The association was replicated in men ( N = 1554, P = 0.045) in an independent dataset. This locus was previously reported to be associated with human height and with self-reported snoring. We also identified rs13087058 on chromosome 3 as a suggestive locus in sex-combined analysis ( N = 15090, P = 2.94 × 10 −7 replication P =0.049). This locus was also associated with electrocardiogram-assessed PR interval and is a cis-expression quantitative locus for the PDZ Domain-containing ring finger 2 ( PDZRN3 ) gene. Both NOG and PDZRN3 interact with members of transforming growth factor-beta superfamily signaling proteins. Our study suggests that neck circumference may have unique genetic basis independent of BMI.
Publisher: Elsevier BV
Date: 11-2019
No related grants have been discovered for Tamar Sofer.