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  • 1
    Online Resource
    Online Resource
    Pleiotropic effects of telomere length loci with brain morphology and brain tissue expression
    Oxford University Press (OUP) ; 2021
    In:  Human Molecular Genetics Vol. 30, No. 14 ( 2021-06-26), p. 1360-1370
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 30, No. 14 ( 2021-06-26), p. 1360-1370
    Abstract: Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. Although telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively, with brain morphology measures for 101 T1-magnetic resonance imaging-based region of interests (n = 21 821). The posterior probability ( & gt;90%) was observed for ‘fourth ventricle’, ‘gray matter’ and ‘cerebellar vermal lobules I–IV’ volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = four genes; EUR = five genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (P ≤ 2.47 × 10−6). Integrating chromatin profiles with LTL-single nucleotide polymorphisms identified 45 genes (EUR) and 79 genes (EAS) (P ≤ 9.78×10−7). We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes—GPR37, OBFC1 and RTEL1/RTEL1-TNFRSF6B—show convergent evidence of pleiotropy with brain morphology, gene and methylation expression and chromatin association. Mapping gene functions to drug–gene interactions, we identified process ‘transmission across chemical synapses’ (P  & lt; 2.78 × 10−4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    URL: Article
    DOI: 10.1093/hmg/ddab102
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    1152 INVESTIGATION ON THE HIGH INCIDENCE OF THE ATTRV-CAUSING TRANSTHYRETIN VARIANT VAL142ILE IN CENTRAL ITALY
    Oxford University Press (OUP) ; 2022
    In:  European Heart Journal Supplements Vol. 24, No. Supplement_K ( 2022-12-15)
    Details
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 24, No. Supplement_K ( 2022-12-15)
    Abstract: The p.Val142Ile variant in transthyretin (encoded by the TTR gene) is the most common genetic cause of transthyretin-related amyloidosis. This allele is particularly prevalent in communities of African descent compared with populations of different ancestries, where its frequency is two orders of magnitude lower. For this reason, p.Val142Ile has always been considered an “African” variant, with limited studies performed on individuals of European descent. However, recent reports of higher-than-expected prevalence in European-ancestry populations question the African specificity of this allele. Here we show that the high recurrence of p.Val142Ile in central Italy is due to a founder effect and not to recent admixture from African populations, highlighting how this may be the case in other communities. This suggests a probable underestimate of the global prevalence of p.Val142Ile, and further emphasizes the importance of routine inclusion of TTR in gene panels used for clinical genetic testing in hypertrophic cardiomyopathy (independently of the patient's geographical origin), that transthyretin-related amyloidosis can mimic. Figure.Principal Component Analysis (PCA) of the 16 probands together with the 25044 individuals of the 1000 Genomes Project (Phase 3) having been genotyped both within the 1000 Genomes Project (NA10851_1KG) and in-house (NA10851_internal). The proband clustering within the smear of native Americans is A228.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    URL: Article
    DOI: 10.1093/eurheartjsupp/suac121.593
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2141255-8
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  • 3
    Online Resource
    Online Resource
    Multivariate Pattern Analysis of Genotype–Phenotype Relationships in Schizophrenia
    Oxford University Press (OUP) ; 2018
    In:  Schizophrenia Bulletin Vol. 44, No. 5 ( 2018-08-20), p. 1045-1052
    Details
    In: Schizophrenia Bulletin, Oxford University Press (OUP), Vol. 44, No. 5 ( 2018-08-20), p. 1045-1052
    Type of Medium: Online Resource
    ISSN: 0586-7614 , 1745-1701
    URL: Article
    DOI: 10.1093/schbul/sby005
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2180196-4
    SSG: 15,3
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  • 4
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    Online Resource
    Sex differences in the pleiotropy of hearing difficulty with imaging-derived phenotypes: a brain-wide investigation
    Oxford University Press (OUP) ; 2024
    In:  Brain ( 2024-03-08)
    Details
    In: Brain, Oxford University Press (OUP), ( 2024-03-08)
    Abstract: Hearing difficulty (HD) is one of the major health burdens in older adults. While aging-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analyzed a large-scale HD genome-wide association study (GWAS; Ntotal = 501,825, 56% females) and GWAS data related to 3,935 brain imaging-derived phenotypes (IDPs) assessed in up to 33,224 individuals (52% females) using multiple magnetic resonance imaging modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization, and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait colocalization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs. We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 IDPs in males, and 171 IDPs in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven correlations, the causal effects were also confirmed by the Mendelian randomization approach: vessel volume→HD in the sex-combined analysis; hippocampus volume→HD, cerebellum grey matter volume→HD, primary visual cortex volume→HD, and HD→fluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thickness→HD and HD→mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a colocalization signal for the rs13026575 variant between HD, primary visual cortex volume, and SPTBN1 transcriptomic regulation in females. Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awae077
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 5
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    Online Resource
    The association of obesity-related traits on COVID-19 severity and hospitalization is affected by socio-economic status: a multivariable Mendelian randomization study
    Oxford University Press (OUP) ; 2022
    In:  International Journal of Epidemiology Vol. 51, No. 5 ( 2022-10-13), p. 1371-1383
    Details
    In: International Journal of Epidemiology, Oxford University Press (OUP), Vol. 51, No. 5 ( 2022-10-13), p. 1371-1383
    Abstract: Due to its large impact on human health, socio-economic status (SES) could at least partially influence the established association between obesity and coronavirus disease 2019 (COVID-19) severity. To estimate the independent effect of body size and SES on the clinical manifestations of COVID-19, we conducted a Mendelian randomization (MR) study. Methods Applying two-sample MR approaches, we evaluated the effects of body mass index (BMI, n = 322 154), waist circumference (WC, n = 234 069), hip circumference (n = 213 019) and waist–hip ratio (n = 210 088) with respect to three COVID-19 outcomes: severe respiratory COVID-19 (cases = 8779, controls = 1 000 875), hospitalized COVID-19 (cases = 17 992, controls = 1 810 493) and COVID-19 infection (cases = 87 870, controls = 2 210 804). Applying a multivariable MR (MVMR) approach, we estimated the effect of these anthropometric traits on COVID-19 outcomes accounting for the effect of SES assessed as household income (n = 286 301). Results BMI and WC were associated with severe respiratory COVID-19 [BMI: odds ratio (OR) = 1.51, CI = 1.24–1.84, P = 3.01e-05; WC: OR = 1.48, 95% CI = 1.15–1.91, P = 0.0019] and hospitalized COVID-19 (BMI: OR = 1.50, 95% CI = 1.32–1.72, P = 8.83e-10; WC: OR = 1.41, 95% CI = 1.20–1.67, P = 3.72e-05). Conversely, income was associated with lower odds of severe respiratory (OR = 0.70, 95% CI = 0.53–0.93, P = 0.015) and hospitalized COVID-19 (OR = 0.78, 95% CI = 0.66–0.92, P = 0.003). MVMR analyses showed that the effect of these obesity-related traits on increasing the odds of COVID-19 negative outcomes becomes null when accounting for income. Conversely, the association of income with lower odds of COVID-19 negative outcomes is not affected when including the anthropometric traits in the multivariable model. Conclusion Our findings indicate that SES contributes to the effect of obesity-related traits on COVID-19 severity and hospitalization.
    Type of Medium: Online Resource
    ISSN: 0300-5771 , 1464-3685
    URL: Article
    DOI: 10.1093/ije/dyac129
    RVK:
    XF 4100
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1494592-7
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  • 6
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    Online Resource
    Cross-ancestry genome-wide association studies identified heterogeneous loci associated with differences of allele frequency and regulome tagging between participants of European descent and other ancestry groups from the UK Biobank
    Oxford University Press (OUP) ; 2021
    In:  Human Molecular Genetics Vol. 30, No. 15 ( 2021-07-09), p. 1457-1467
    Details
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 30, No. 15 ( 2021-07-09), p. 1457-1467
    Abstract: To investigate cross-ancestry genetics of complex traits, we conducted a phenome-wide analysis of loci with heterogeneous effects across African, Admixed-American, Central/South Asian, East Asian, European and Middle Eastern participants of the UK Biobank (N = 441 331). Testing 843 phenotypes, we identified 82 independent genomic regions mapping variants showing genome-wide significant (GWS) associations (P  & lt; 5 × 10−8) in the trans-ancestry meta-analysis and GWS heterogeneity among the ancestry-specific effects. These included (i) loci with GWS association in one ancestry and concordant but heterogeneous effects among the other ancestries and (ii) loci with a GWS association in one ancestry group and an experiment-wide significant discordant effect (P  & lt; 6.1 × 10−4) in at least another ancestry. Since the trans-ancestry GWS associations were mostly driven by the European ancestry sample size, we investigated the differences of the allele frequency (ΔAF) and linkage disequilibrium regulome tagging (ΔLD) between European populations and the other ancestries. Within loci with concordant effects, the degree of heterogeneity was associated with European–Middle Eastern ΔAF (P = 9.04 × 10−6) and ΔLD of European populations with respect to African, Admixed-American and Central/South Asian groups (P = 8.21 × 10−4, P = 7.17 × 10−4 and P = 2.16 × 10−3, respectively). Within loci with discordant effects, ΔAF and ΔLD of European populations with respect to African and Central/South Asian ancestries were associated with the degree of heterogeneity (ΔAF: P = 7.69 × 10−3 and P = 5.31 × 10−3, ΔLD: P = 0.016 and P = 2.65 × 10−4, respectively). Considering the traits associated with cross-ancestry heterogeneous loci, we observed enrichments for blood biomarkers (P = 5.7 × 10−35) and physical appearance (P = 1.38 × 10−4). This suggests that these specific phenotypic classes may present considerable cross-ancestry heterogeneity owing to large allele frequency and LD variation among worldwide populations.
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    URL: Article
    DOI: 10.1093/hmg/ddab114
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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