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Genome Medicine Aug 2021Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from...
BACKGROUND
Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood.
METHODS
We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function.
RESULTS
Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network.
CONCLUSIONS
Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.
Topics: Adipocytes; Adipose Tissue; Adiposity; Aged; Algorithms; Biomarkers; Body Mass Index; Cells, Cultured; Computational Biology; Diabetes Mellitus, Type 2; Disease Susceptibility; Gene Expression Profiling; Gene Expression Regulation; Gene Knockdown Techniques; Gene Regulatory Networks; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Lod Score; Male; Middle Aged; Obesity, Abdominal; T-Box Domain Proteins; Trans-Activators; Waist-Hip Ratio
PubMed: 34340684
DOI: 10.1186/s13073-021-00939-2 -
Methods in Molecular Biology (Clifton,... 2017Linkage analysis is a statistical genetics method to localize disease and trait genes to specific chromosome regions. The analysis requires pedigrees with members who...
Linkage analysis is a statistical genetics method to localize disease and trait genes to specific chromosome regions. The analysis requires pedigrees with members who vary among each other in the trait of interest and who have been genotyped with known genetic markers. Linkage analysis tests whether any of the marker alleles cosegregate with the disease or trait within the pedigree. Evidence of cosegregation is then combined across the families. We describe here the background and methods to conduct a linkage analysis for a binary trait, such as a disease, when the model of the gene contributing to the trait can be formulated. There are a number of statistical genetics software packages that allow you conduct a model-based linkage analysis of a binary trait. We describe in great detail how to run one of the programs, the LODLINK program of the Statistical Analysis for Genetic Epidemiology (S.A.G.E.) package. We provide directions for making the four input files and information on how to access and interpret the output files. We then discuss more complex analyses that can be conducted. We discuss the MLOD program for multipoint linkage analysis, including its relation to LODLINK and the additional file needed. Notes to improve your ability to run the program are included.
Topics: Chromosome Mapping; Chromosomes, Human; Female; Genetic Linkage; Genetic Loci; Genetic Markers; Genetic Predisposition to Disease; Humans; Lod Score; Male; Models, Genetic; Molecular Epidemiology; Pedigree; Phenotype; Quantitative Trait Loci; Recombination, Genetic; Software
PubMed: 28980252
DOI: 10.1007/978-1-4939-7274-6_15 -
Diabetes/metabolism Research and Reviews Feb 2020To investigate the genetic factors contributing to early-onset type 2 diabetes (EOD) in the Chinese Hans populations.
AIMS
To investigate the genetic factors contributing to early-onset type 2 diabetes (EOD) in the Chinese Hans populations.
MATERIALS AND METHODS
For 2734 newly diagnosed type 2 diabetes patients and 4041 normal glycemic controls, 25 single nucleotide polymorphisms from 24 genomic loci linked to diabetes were successfully genotyped. Three genetic risk scores (GRSs) were constructed, including the weighted type 2 diabetes-related GRS (wT-GRS), the weighted β-cell function-related GRS (wB-GRS), and the weighted GRS constructed by risk alleles not related to β-cell function (wNB-GRS). For patients with diabetes, EOD, middle-age-onset type 2 diabetes (MOD), and late-onset type 2 diabetes (LOD) were defined by onset ages ≤40, 40 to 60, and ≥60 years, respectively.
RESULTS
From single marker analysis, different gene profiles were identified between EOD and LOD patients. EOD patients had greater wT-GRS and wB-GRS values than LOD patients. After adjustment for sex, elevated wT-GRS and wB-GRS values were significantly associated with an increased risk for EOD by 1.11- and 1.21-fold per allele (P = 1.69 × 10 ; 6.07 × 10 ). The wT-GRS and wNB-GRS were nominally related to an increased risk of LOD by 1.03-fold per allele (P = 1.03 × 10 , 1.78 × 10 ). In patients with diabetes, higher wT-GRS and wB-GRS were associated with younger onset age [wT-GRS: β (SE) = -0.0033(0.0016), P = 3.74 × 10 ; wB-GRS: -0.0076(0.0028), 7.45 × 10 ] and decreased insulinogenic index [wT-GRS: -0.0384(0.0098), 9.39 × 10 ; wB-GRS: -0.0722(0.0176), 4.21 × 10 ].
CONCLUSION
Our findings indicate a strong genetic predisposition for EOD, which can be mainly attributed to genetic variants linked to β-cell function, suggesting the β-cell dysfunction plays a key role in the pathogenesis of EOD in Chinese Han individuals.
Topics: Adult; Age of Onset; Aged; Asian People; Biomarkers; China; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Incidence; Male; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Risk Factors
PubMed: 31465628
DOI: 10.1002/dmrr.3214 -
Atherosclerosis Jan 2020Oxidative stress is associated with cardiometabolic traits in observational studies, yet the underlying causal relationship remains unclear. Apolipoprotein E-deficient...
BACKGROUND AND AIMS
Oxidative stress is associated with cardiometabolic traits in observational studies, yet the underlying causal relationship remains unclear. Apolipoprotein E-deficient (Apoe) mice develop significant hyperlipidemia and hyperglycemia on a Western diet. Here we conducted linkage analysis to investigate genetic connections between cardiometabolic traits and oxidative stress.
METHODS
266 female F2 mice were generated from an intercross between C57BL/6 (B6) and BALB/c (BALB) Apoe mice and fed 12 weeks of Western diet. Plasma levels of HDL, LDL cholesterol, triglycerides, glucose and malondialdehyde (MDA) and atherosclerosis in aortic root and left carotid artery were measured. 127 microsatellite markers across the genome were genotyped.
RESULTS
One significant locus at 78.3 cM on chromosome (Chr) 1 (LOD score: 3.85), named Mda1, and two suggestive loci near 60.3 cM on Chr1 (LOD score: 2.32, named Mda2 due to replication in a separate cross) and 19.6 cM on Chr4 (LOD score: 2.34) were identified for MDA levels. Mda1 coincided precisely with loci for LDL, triglyceride, glucose, and body weight and overlapped with a locus for atherosclerosis in the aortic root. Plasma LDL, triglyceride, and glucose explained 25.5, 19.2, and 24.2% of the variation in MDA levels of F2 mice, respectively. After correction for triglyceride or LDL, QTLs for MDA on Chr1 and Chr4 disappeared. QTLs on Chr1 disappeared, remained on Chr4, and additional QTLs on Chr12 and Chr13 were detected after correction for glucose. The QTL on Chr12, named Mda3, had a significant LOD score of 8.034 and peaked 62.22 at cM.
CONCLUSIONS
We demonstrated a causative role for cardiometabolic traits in oxidative stress and identified hyperlipidemia and hyperglycemia as a major driver of oxidative stress.
Topics: Animals; Apolipoproteins E; Cholesterol, LDL; Crosses, Genetic; Disease Models, Animal; Female; Genetic Linkage; Genotype; Hyperlipidemias; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Triglycerides
PubMed: 31821957
DOI: 10.1016/j.atherosclerosis.2019.11.034 -
Journal of Medical Genetics Sep 2022Auriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia...
BACKGROUND
Auriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway (, and ) and some cases remain unsolved. Here we studied a large unsolved four-generation family.
METHODS
We performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells.
RESULTS
This study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes , which is located over 200 kb telomeric to the top candidate gene . Notably, Capture-C analysis revealed multiple cis interactions between the promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of and its neighbouring gene, , in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells.
CONCLUSION
Our findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of expression during craniofacial development can contribute to the phenotype.
Topics: Ear; Ear Diseases; Humans; Nuclear Proteins; Osteogenesis; Regulatory Sequences, Nucleic Acid; Twist-Related Protein 1
PubMed: 34750192
DOI: 10.1136/jmedgenet-2021-107825 -
International Journal of Molecular... Nov 2023Rice plant height is an agricultural trait closely related to biomass, lodging tolerance, and yield. Identifying quantitative trait loci (QTL) regions related to plant...
Rice plant height is an agricultural trait closely related to biomass, lodging tolerance, and yield. Identifying quantitative trait loci (QTL) regions related to plant height regulation and developing strategies to screen potential candidate genes can improve agricultural traits in rice. In this study, a double haploid population (CNDH), derived by crossing 'Cheongcheong' and 'Nagdong' individuals, was used, and a genetic map was constructed with 222 single-sequence repeat markers. In the RM3482-RM212 region on chromosome 1, , , , , and were identified for five consecutive years. The phenotypic variance explained ranged from 9.3% to 13.1%, and the LOD score ranged between 3.6 and 17.6. , a candidate gene related to plant height regulation, was screened in RM3482-RM212. is an ortholog of gibberellin 20 oxidase 2, and its haplotype was distinguished by nine SNPs. Plants were divided into two groups based on their height, and tall and short plants were distinguished and clustered according to the expression level of . QTLs and candidate genes related to plant height regulation, and thus, biomass regulation, were screened and identified in this study, but the molecular mechanism of the regulation remains poorly known. The information obtained in this study will help develop molecular markers for marker-assisted selection and breeding through rice plant height control.
Topics: Humans; Quantitative Trait Loci; Chromosome Mapping; Oryza; Plant Breeding; Phenotype
PubMed: 38069217
DOI: 10.3390/ijms242316895 -
Neurobiology of Aging Nov 2015We compared cortical thickness between patients with late-life depression (LLD) and healthy controls and between patients with early-onset (EOD) and late-onset (LOD)...
We compared cortical thickness between patients with late-life depression (LLD) and healthy controls and between patients with early-onset (EOD) and late-onset (LOD) depression. We also tested age effects on cortical thickness in LLD and controls and if cortical thickness and hippocampal volumes were associated with cognitive performance in LLD. Three-dimensional T1-weighted magnetic resonance images were obtained in 49 LLD and 49 matched hospital controls and processed using FreeSurfer. General linear model analysis was used as a statistical approach. LLD group had thinning in the left parahippocampal, fusiform, and inferior-parietal cortex compared with controls. Age correlated with cortical thinning in controls but not in LLD. Women in the LOD groups had extensive cortical thinning in the lateral prefrontal cortex bilaterally compared with EOD women. Absence of statistically significant changes observed in men should however be treated with caution because of the low number of men in the study. Mini-Mental Status Examination score correlated with lateral prefrontal cortical thickness bilaterally and hippocampal volume in the total group of LLD and in LOD but not EOD. LLD is associated with cortical thinning, which is associated with age at depression onset, gender, and level of cognitive functioning.
Topics: Aged; Aged, 80 and over; Aging; Atrophy; Cerebral Cortex; Cognition; Depression; Female; Hippocampus; Humans; Late Onset Disorders; Magnetic Resonance Angiography; Male; Neuropsychological Tests; Organ Size; Prefrontal Cortex
PubMed: 26277679
DOI: 10.1016/j.neurobiolaging.2015.04.020 -
Nature Reviews. Genetics May 2015For many years, linkage analysis was the primary tool used for the genetic mapping of Mendelian and complex traits with familial aggregation. Linkage analysis was... (Review)
Review
For many years, linkage analysis was the primary tool used for the genetic mapping of Mendelian and complex traits with familial aggregation. Linkage analysis was largely supplanted by the wide adoption of genome-wide association studies (GWASs). However, with the recent increased use of whole-genome sequencing (WGS), linkage analysis is again emerging as an important and powerful analysis method for the identification of genes involved in disease aetiology, often in conjunction with WGS filtering approaches. Here, we review the principles of linkage analysis and provide practical guidelines for carrying out linkage studies using WGS data.
Topics: Algorithms; Female; Genetic Linkage; Genome, Human; Genome-Wide Association Study; Genotyping Techniques; Humans; Lod Score; Male; Pedigree; Penetrance; Phenotype; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Software
PubMed: 25824869
DOI: 10.1038/nrg3908 -
Sensitivity and performance of three novel quantitative assays of SARS-CoV-2 nucleoprotein in blood.Scientific Reports Feb 2023To assess if SARS-CoV-2 (COVID-19) systemic disease can be determined by available nucleoprotein assays, we compared the performance of three commercial SARS-CoV-2...
To assess if SARS-CoV-2 (COVID-19) systemic disease can be determined by available nucleoprotein assays, we compared the performance of three commercial SARS-CoV-2 nucleoprotein (N) assays in plasma. A total of 272 plasma samples collected in the period November-December 2021 were analyzed by the methods Simoa SARS CoV-2 N Protein Advantage Kit [Quanterix Simoa], Solsten SARS-CoV-2 Antigen enzyme immunosorbent assay (ELISA) [Solsten ELISA], and Elecsys SARS-CoV-2 Antigen electrochemiluminescence immunoassay [Elecsys ECLIA]. Additionally, a dilution series of inactivated virus culture was analyzed by the three assays. The SARS CoV-2 PCR-status was not known for the patients. Linear correlation in the pairwise correlation between assays as well as linearity of dilution series of inactivated virus culture was estimated by Spearman score. Sensitivity and specificity were estimated by pairwise comparison. The three assays showed poor agreement on patient samples with regards to concentration. Performance on virus culture was excellent but with different level of detection (LOD). Positive vs negative results show comparable sensitivity and specificity of Quanterix Simoa and Solsten ELISA, with a higher LOD in Elecsys ECLIA and thus lower sensitivity and high specificity. N by all tested assays can be used as a marker for systemic COVID-19 disease.
Topics: Humans; SARS-CoV-2; COVID-19; Plasma; Biological Assay; Immunosorbents; Nucleoproteins
PubMed: 36806155
DOI: 10.1038/s41598-023-29973-3 -
Clinical Genetics Jul 2022Congenital anomalies of the kidney and urinary tract (CAKUT) are a spectrum of abnormalities affecting morphogenesis of the kidneys and other structures of the urinary...
Congenital anomalies of the kidney and urinary tract (CAKUT) are a spectrum of abnormalities affecting morphogenesis of the kidneys and other structures of the urinary tract. Bilateral renal agenesis (BRA) is the most severe presentation of CAKUT. Loss of either nephronectin (NPNT) or its receptor ITGA8 leads to failure of metanephric kidney development with resulting renal agenesis in murine models. Very recently, a single family with renal agenesis and a homozygous truncating variant in NPNT was reported. We report two families in whom genome-wide linkage analysis showed an autozygous locus linked to BRA (at least one member has unilateral renal agenesis) at 4q24, with an LOD score of ~3. Exome sequencing detected a nonsense variant in NPNT in both families within the linkage interval. The pathogenicity of this variant was supported by reverse transcription polymerase chain reaction data showing complete nonsense-mediated decay of the NPNT transcript. Our report confirms the candidacy of NPNT in renal agenesis in humans and shows that even complete loss of function can be compatible with the formation of a single kidney.
Topics: Animals; Congenital Abnormalities; Extracellular Matrix Proteins; Humans; Kidney; Kidney Diseases; Mice; Solitary Kidney; Urogenital Abnormalities; Vesico-Ureteral Reflux
PubMed: 35246978
DOI: 10.1111/cge.14128