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  • 1
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    De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Abstract: De novo mutations (DNMs), or mutations that appear in an individual 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 diverse 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 samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains 〈 1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, 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.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902766117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
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    Lung tissue shows divergent gene expression between chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis
    Springer Science and Business Media LLC ; 2022
    In:  Respiratory Research Vol. 23, No. 1 ( 2022-12)
    Details
    In: Respiratory Research, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2022-12)
    Abstract: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are characterized by shared exposures and clinical features, but distinct genetic and pathologic features exist. These features have not been well-studied using large-scale gene expression datasets. We hypothesized that there are divergent gene, pathway, and cellular signatures between COPD and IPF. Methods We performed RNA-sequencing on lung tissues from individuals with IPF (n = 231) and COPD (n = 377) compared to control (n = 267), defined as individuals with normal spirometry. We grouped the overlapping differential expression gene sets based on direction of expression and examined the resultant sets for genes of interest, pathway enrichment, and cell composition. Using gene set variation analysis, we validated the overlap group gene sets in independent COPD and IPF data sets. Results We found 5010 genes differentially expressed between COPD and control, and 11,454 genes differentially expressed between IPF and control (1% false discovery rate). 3846 genes overlapped between IPF and COPD. Several pathways were enriched for genes upregulated in COPD and downregulated in IPF; however, no pathways were enriched for genes downregulated in COPD and upregulated in IPF. There were many myeloid cell genes with increased expression in COPD but decreased in IPF. We found that the genes upregulated in COPD but downregulated in IPF were associated with lower lung function in the independent validation cohorts. Conclusions We identified a divergent gene expression signature between COPD and IPF, with increased expression in COPD and decreased in IPF. This signature is associated with worse lung function in both COPD and IPF.
    Type of Medium: Online Resource
    ISSN: 1465-993X
    URL: Article
    DOI: 10.1186/s12931-022-02013-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2041675-1
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  • 3
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    A unifying framework for rare variant association testing in family-based designs, including higher criticism approaches, SKATs, and burden tests
    Oxford University Press (OUP) ; 2021
    In:  Bioinformatics Vol. 36, No. 22-23 ( 2021-04-01), p. 5432-5438
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 36, No. 22-23 ( 2021-04-01), p. 5432-5438
    Abstract: Analysis of rare variants in family-based studies remains a challenge. Transmission-based approaches provide robustness against population stratification, but the evaluation of the significance of test statistics based on asymptotic theory can be imprecise. Also, power will depend heavily on the choice of the test statistic and on the underlying genetic architecture of the locus, which will be generally unknown. Results In our proposed framework, we utilize the FBAT haplotype algorithm to obtain the conditional offspring genotype distribution under the null hypothesis given the sufficient statistic. Based on this conditional offspring genotype distribution, the significance of virtually any association test statistic can be evaluated based on simulations or exact computations, without the need for asymptotic approximations. Besides standard linear burden-type statistics, this enables our approach to also evaluate other test statistics such as variance components statistics, higher criticism approaches, and maximum-single-variant-statistics, where asymptotic theory might be involved or does not provide accurate approximations for rare variant data. Based on these P-values, combined test statistics such as the aggregated Cauchy association test (ACAT) can also be utilized. In simulation studies, we show that our framework outperforms existing approaches for family-based studies in several scenarios. We also applied our methodology to a TOPMed whole-genome sequencing dataset with 897 asthmatic trios from Costa Rica. Availability and implementation FBAT software is available at https://sites.google.com/view/fbatwebpage. Simulation code is available at https://github.com/julianhecker/FBAT_rare_variant_test_simulations. Whole-genome sequencing data for ‘NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica’ is available at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000988.v4.p1. Supplementary information Supplementary data are available at Bioinformatics online.
    Type of Medium: Online Resource
    ISSN: 1367-4803 , 1367-4811
    URL: Article
    DOI: 10.1093/bioinformatics/btaa1055
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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    SSG: 12
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  • 4
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    Polygenic risk scores identify heterogeneity in asthma and chronic obstructive pulmonary disease
    Elsevier BV ; 2023
    In:  Journal of Allergy and Clinical Immunology ( 2023-8)
    Details
    In: Journal of Allergy and Clinical Immunology, Elsevier BV, ( 2023-8)
    Type of Medium: Online Resource
    ISSN: 0091-6749
    URL: Article
    DOI: 10.1016/j.jaci.2023.08.002
    RVK:
    XA 52000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2006613-2
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  • 5
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    Intrauterine Smoke Exposure, microRNA Expression during Human Lung Development, and Childhood Asthma
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 9 ( 2023-04-23), p. 7727-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 9 ( 2023-04-23), p. 7727-
    Abstract: Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development. We hypothesized that miRNA–mRNA networks are dysregulated by IUS during human lung development and that these miRNAs may be associated with future risk of asthma and allergy. Human fetal lung samples from a prenatal tissue retrieval program were tested for differential miRNA expression with IUS exposure (measured using placental cotinine concentration). RNA was extracted and miRNA-sequencing was performed. We performed differential expression using IUS exposure, with covariate adjustment. We also considered the above model with an additional sex-by-IUS interaction term, allowing IUS effects to differ by male and female samples. Using paired gene expression profiles, we created sex-stratified miRNA–mRNA correlation networks predictive of IUS using DIABLO. We additionally evaluated whether miRNAs were associated with asthma and allergy outcomes in a cohort of childhood asthma. We profiled pseudoglandular lung miRNA in n = 298 samples, 139 (47%) of which had evidence of IUS exposure. Of 515 miRNAs, 25 were significantly associated with intrauterine smoke exposure (q-value 〈 0.10). The IUS associated miRNAs were correlated with well-known asthma genes (e.g., ORM1-Like Protein 3, ORDML3) and enriched in disease-relevant pathways (oxidative stress). Eleven IUS-miRNAs were also correlated with clinical measures (e.g., Immunoglobulin E andlungfunction) in children with asthma, further supporting their likely disease relevance. Lastly, we found substantial differences in IUS effects by sex, finding 95 significant IUS-miRNAs in male samples, but only four miRNAs in female samples. The miRNA–mRNA correlation networks were predictive of IUS (AUC = 0.78 in males and 0.86 in females) and suggested that IUS-miRNAs are involved in regulation of disease-relevant genes (e.g., A disintegrin and metalloproteinase domain 19 (ADAM19), LBH regulator of WNT signaling (LBH)) and sex hormone signaling (Coactivator associated methyltransferase 1(CARM1)). Our study demonstrated differential expression of miRNAs by IUS during early prenatal human lung development, which may be modified by sex. Based on their gene targets and correlation to clinical asthma and atopy outcomes, these IUS-miRNAs may be relevant for subsequent allergy and asthma risk. Our study provides insight into the impact of IUS in human fetal lung transcriptional networks and on the developmental origins of asthma and allergic disorders.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24097727
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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