| 1. |
- Aguila, Monica, et al.
(författare)
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AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity
- 2020
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Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 29:8, s. 1310-1318
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Tidskriftsartikel (refereegranskat)abstract
- Rhodopsin misfolding caused by the P23H mutation is a major cause of autosomal dominant retinitis pigmentosa (adRP). To date, there are no effective treatments for adRP. The BiP co-chaperone and reductase ERdj5 (DNAJC10) is part of the endoplasmic reticulum (ER) quality control machinery, and previous studies have shown that overexpression of ERdj5 in vitro enhanced the degradation of P23H rhodopsin, whereas knockdown of ERdj5 increased P23H rhodopsin ER retention and aggregation. Here, we investigated the role of ERdj5 in photoreceptor homeostasis in vivo by using an Erdj5 knockout mouse crossed with the P23H knock-in mouse and by adeno-associated viral (AAV) vector-mediated gene augmentation of ERdj5 in P23H-3 rats. Electroretinogram (ERG) and optical coherence tomography of Erdj5(-/-) and P23H(+/-):Erdj5(-/-) mice showed no effect of ERdj5 ablation on retinal function or photoreceptor survival. Rhodopsin levels and localization were similar to those of control animals at a range of time points. By contrast, when AAV2/8-ERdj5-HA was subretinally injected into P23H-3 rats, analysis of the full-field ERG suggested that overexpression of ERdj5 reduced visual function loss 10 weeks post-injection (PI). This correlated with a significant preservation of photoreceptor cells at 4 and 10 weeks PI. Assessment of the outer nuclear layer (ONL) morphology showed preserved ONL thickness and reduced rhodopsin retention in the ONL in the injected superior retina. Overall, these data suggest that manipulation of the ER quality control and ER-associated degradation factors to promote mutant protein degradation could be beneficial for the treatment of adRP caused by mutant rhodopsin.
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| 2. |
- Ahluwalia, T. S., et al.
(författare)
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Genome-wide association study of circulating interleukin 6 levels identifies novel loci
- 2021
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 30:5, s. 393-409
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Tidskriftsartikel (refereegranskat)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 67428 (n(discovery)=52654 and n(replication)=14774) individuals 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, (P-combined=1.8x10(-11)), HLA-DRB1/DRB5 rs660895 on Chr6p21 (P-combined=1.5x10(-10)) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (P-combined=1.2x10(-122)). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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| 3. |
- Beck, J. J., et al.
(författare)
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Genetic meta-analysis of twin birth weight shows high genetic correlation with singleton birth weight
- 2021
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 30:19, s. 1894-1905
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Tidskriftsartikel (refereegranskat)abstract
- Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [r(g)]= 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.
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| 4. |
- Bicak, Mesude, et al.
(författare)
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Prostate cancer risk SNP rs10993994 is a trans-eQTL for SNHG11 mediated through MSMB
- 2020
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 29:10, s. 1581-1591
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Tidskriftsartikel (refereegranskat)abstract
- How genome-wide association studies-identified single-nucleotide polymorphisms (SNPs) affect remote genes remains unknown. Expression quantitative trait locus (eQTL) association meta-analysis on 496 prostate tumor and 602 normal prostate samples with 117 SNPs revealed novel cis-eQTLs and trans-eQTLs. Mediation testing and colocalization analysis demonstrate that MSMB is a cis-acting mediator for SNHG11 (P < 0.01). Removing rs10993994 in LNCaP cell lines by CRISPR/Cas9 editing shows that the C-allele corresponds with an over 100-fold increase in MSMB expression and 5-fold increase in SNHG11 compared with the T-allele. Colocalization analysis confirmed that the same set of SNPs associated with MSMB expression is associated with SNHG11 expression (posterior probability of shared variants is 66.6% in tumor and 91.4% in benign). These analyses further demonstrate variants driving MSMB expression differ in tumor and normal, suggesting regulatory network rewiring during tumorigenesis.
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| 5. |
- Brazdis, Razvan Marius, et al.
(författare)
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Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease
- 2020
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 29:7, s. 1180-1191
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDANs and cortical projection neurons (CPNs). SNCA dosage increase did not influence the differentiation efficiency of mDANs and CPNs. However, elevated α-Syn pathology, as revealed by enhanced α-Syn insolubility and phosphorylation, was determined in PD-derived mDANs compared with PD CPNs. PD-derived mDANs exhibited higher levels of reactive oxygen species and protein nitration levels compared with CPNs, which might underlie elevated α-Syn pathology observed in mDANs. Finally, increased neuronal death was observed in PD-derived mDANs compared to PD CPNs and to control mDANs and CPNs. Our results reveal, for the first time, a higher α-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDANs compared with PD CPNs from the same patient. The finding implies the contribution of pathogenic α-Syn, probably induced by oxidative stress, to selective vulnerability of substantia nigra dopaminergic neurons in human PD.
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| 6. |
- Černý, Viktor, et al.
(författare)
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Demographic history and admixture dynamics in African Sahelian populations
- 2021
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 30:R1, s. R29-R36
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Forskningsöversikt (refereegranskat)abstract
- The Sahel/Savannah belt of Africa is a contact zone between two subsistence systems (nomadic pastoralism and sedentary farming) and of two groups of populations, namely Eurasians penetrating from northern Africa southwards and sub-Saharan Africans migrating northwards. Because pastoralism is characterized by a high degree of mobility, it leaves few significant archaeological traces. Demographic history seen through the lens of population genetic studies complements our historical and archaeological knowledge in this African region. In this review, we highlight recent advances in our understanding of demographic history in the Sahel/Savannah belt as revealed by genetic studies. We show the impact of food-producing subsistence strategies on population structure and the somewhat different migration patterns in the western and eastern part of the region. Genomic studies show that the gene pool of various groups of Sahelians consists in a complex mosaic of several ancestries. We also touch upon various signals of genetic adaptations such as lactase persistence, taste sensitivity and malaria resistance, all of which have different distribution patterns among Sahelian populations. Overall, genetic studies contribute to gain a deeper understanding about the demographic and adaptive history of human populations in this specific African region and beyond.
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| 7. |
- Choudhury, Ananyo, et al.
(författare)
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Bantu-speaker migration and admixture in southern Africa
- 2021
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 30:R1, s. R56-R63
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Forskningsöversikt (refereegranskat)abstract
- The presence of Early and Middle Stone Age human remains and associated archeological artifacts from various sites scattered across southern Africa, suggests this geographic region to be one of the first abodes of anatomically modern humans. Although the presence of hunter-gatherer cultures in this region dates back to deep times, the peopling of southern Africa has largely been reshaped by three major sets of migrations over the last 2000 years. These migrations have led to a confluence of four distinct ancestries (San hunter-gatherer, East-African pastoralist, Bantu-speaker farmer and Eurasian) in populations from this region. In this review, we have summarized the recent insights into the refinement of timelines and routes of the migration of Bantu-speaking populations to southern Africa and their admixture with resident southern African Khoe-San populations. We highlight two recent studies providing evidence for the emergence of fine-scale population structure within some South-Eastern Bantu-speaker groups. We also accentuate whole genome sequencing studies (current and ancient) that have both enhanced our understanding of the peopling of southern Africa and demonstrated a huge potential for novel variant discovery in populations from this region. Finally, we identify some of the major gaps and inconsistencies in our understanding and emphasize the importance of more systematic studies of southern African populations from diverse ethnolinguistic groups and geographic locations.
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| 8. |
- Cruz, Raquel, et al.
(författare)
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Novel genes and sex differences in COVID-19 severity
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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| 9. |
- Dahlqvist, Johanna, 1979-, et al.
(författare)
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Systematic identification of genomic elements that regulate FCGR2A expression and harbor variants linked with autoimmune disease
- 2021
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083.
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Tidskriftsartikel (refereegranskat)abstract
- Background: FCGR2A binds antibody–antigen complexes to regulate the abundance of circulating and deposited complexes along with downstream immune and autoimmune responses. Although the abundance of FCRG2A may be critical in immune-mediated diseases, little is known about whether its surface expression is regulated through cis genomic elements and non-coding variants. In the current study, we aimed to characterize the regulation of FCGR2A expression, the impact of genetic variation and its association with autoimmune disease. Methods: We applied CRISPR-based interference and editing to scrutinize 1.7 Mb of open chromatin surrounding the FCGR2A gene to identify regulatory elements. Relevant transcription factors (TFs) binding to these regions were defined through public databases. Genetic variants affecting regulation were identified using luciferase reporter assays and were verified in a cohort of 1996 genotyped healthy individuals using flow cytometry. Results: We identified a complex proximal region and five distal enhancers regulating FCGR2A. The proximal region split into subregions upstream and downstream of the transcription start site, was enriched in binding of inflammation-regulated TFs, and harbored a variant associated with FCGR2A expression in primary myeloid cells. One distal enhancer region was occupied by CCCTC-binding factor (CTCF) whose binding site was disrupted by a rare genetic variant, altering gene expression. Conclusions: The FCGR2A gene is regulated by multiple proximal and distal genomic regions, with links to autoimmune disease. These findings may open up novel therapeutic avenues where fine-tuning of FCGR2A levels may constitute a part of treatment strategies for immune-mediated diseases.
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| 10. |
- Davis, Kasey N., et al.
(författare)
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Mutations in human DNA methyltransferase DNMT1 induce specific genome-wide epigenomic and transcriptomic changes in neurodevelopment
- 2023
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 32:21, s. 3105-3120
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Tidskriftsartikel (refereegranskat)abstract
- DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPSCs) and induced neurons (iNs) generated from patients with ADCA-DN and controls, to explore the epigenomic and transcriptomic effects of mutations in DNMT1. We show cell type–specific changes in gene expression and DNA methylation patterns. DNA methylation and gene expression changes were negatively correlated in iPSCs and iNs. In addition, we identified a group of genes associated with clinical phenotypes of ADCA-DN, including PDGFB and PRDM8 for cerebellar ataxia, psychosis and dementia and NR2F1 for deafness and optic atrophy. Furthermore, ZFP57, which is required to maintain gene imprinting through DNA methylation during early development, was hypomethylated in promoters and exhibited upregulated expression in patients with ADCA-DN in both iPSC and iNs. Our results provide insight into the functions of DNMT1 and the molecular changes associated with ADCA-DN, with potential implications for genes associated with related phenotypes.
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| 11. |
- de Jong, Sarah, et al.
(författare)
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Effect of rare coding variants in the CFI gene on Factor I expression levels
- 2020
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 29:14, s. 2313-2324
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Tidskriftsartikel (refereegranskat)abstract
- Factor I (FI) is one of the main inhibitors of complement activity, and numerous rare coding variants have been reported in patients with age-related macular degeneration, atypical hemolytic uremic syndrome and C3 glomerulopathy. Since many of these variants are of unknown clinical significance, this study aimed to determine the effect of rare coding variants in the complement factor I (CFI) gene on FI expression. We measured FI levels in plasma samples of carriers of rare coding variants and in vitro in the supernatants of epithelial cells expressing recombinant FI. FI levels were measured in 177 plasma samples of 155 individuals, carrying 24 different rare coding variants in CFI. In carriers of the variants p.Gly119Arg, p.Leu131Arg, p.Gly188Ala and c.772G>A (r.685_773del), significantly reduced FI plasma levels were detected. Furthermore, recombinant FI expression levels were determined for 126 rare coding variants. Of these variants 68 (54%) resulted in significantly reduced FI expression in supernatant compared to wildtype (WT). The recombinant protein expression levels correlated significantly with the FI level in plasma of carriers of CFI variants. In this study, we performed the most comprehensive FI expression level analysis of rare coding variants in CFI to date. More than half of CFI variants lead to reduced FI expression, which might impair complement regulation in vivo. Our study will aid the interpretation of rare coding CFI variants identified in clinical practice, which is in particular important in light of patient inclusion in ongoing clinical trials for CFI gene supplementation in AMD.
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| 12. |
- Fitipaldi, Hugo, et al.
(författare)
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Ethnic, gender and other sociodemographic biases in genome-wide association studies for the most burdensome non-communicable diseases : 2005-2022
- 2023
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 32:3, s. 520-532
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Since 2005, disease-related human genetic diversity has been intensively characterized using genome-wide association studies (GWAS). Understanding how and by whom this work was performed may yield valuable insights into the generalizability of GWAS discoveries to global populations and how high-impact genetics research can be equitably sustained in the future.MATERIALS AND METHODS: We mined the NHGRI-EBI GWAS Catalog (2005-2022) for the most burdensome non-communicable causes of death worldwide. We then compared: i) the geographic, ethnic, and socioeconomic characteristics of study populations, ii) the geographic and socioeconomic characteristics of the regions within which researchers were located, and iii) the extent to which male and female investigators undertook and led the research.RESULTS: The research institutions leading the work are often US-based (37%), while the origin of samples is more diverse, with the Nordic countries having contributed as much data to GWAS as the USA (~17% of data). The majority of first (60%), senior (75%) and all (66%) authors are male; although proportions vary by disease and leadership level, male coauthors are the ubiquitous majority. The vast majority (92%) of complex trait GWAS has been performed in European ancestry populations, with cohorts and scientists predominantly located in medium-to-high socioeconomically ranked countries; apart from East Asians (~5%), other ethnicities rarely feature in published GWAS.CONCLUSION: Most GWAS cohorts are of European ancestry residing outside the US, with a smaller yet meaningful proportion of East Asian ancestry. Papers describing GWAS research are predominantly authored by male scientists based in medium-to-high income countries.
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| 13. |
- Fortes-Lima, Cesar, PhD, 1985-, et al.
(författare)
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Anthropological genetics perspectives on the transatlantic slave trade
- 2021
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 30:R1, s. R79-R87
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Forskningsöversikt (refereegranskat)abstract
- During the Trans-Atlantic Slave Trade (TAST), around twelve million Africans were enslaved and forcibly moved from Africa to the Americas and Europe, durably influencing the genetic and cultural landscape of a large part of humanity since the 15th century. Following historians, archaeologists, and anthropologists, population geneticists have, since the 1950's mainly, extensively investigated the genetic diversity of populations on both sides of the Atlantic. These studies shed new lights into the largely unknown genetic origins of numerous enslaved-African descendant communities in the Americas, by inferring their genetic relationships with extant African, European, and Native American populations. Furthermore, exploring genome-wide data with novel statistical and bioinformatics methods, population geneticists have been increasingly able to infer the last 500 years of admixture histories of these populations. These inferences have highlighted the diversity of histories experienced by enslaved-African descendants, and the complex influences of socioeconomic, political, and historical contexts on human genetic diversity patterns during and after the slave trade. Finally, the recent advances of paleogenomics unveiled crucial aspects of the life and health of the first generation of enslaved-Africans in the Americas. Altogether, human population genetics approaches in the genomic and paleogenomic era need to be coupled with history, archaeology, anthropology, and demography in interdisciplinary research, to reconstruct the multifaceted and largely unknown history of the TAST and its influence on human biological and cultural diversities today. Here, we review anthropological genomics studies published over the past 15 years and focusing on the history of enslaved-African descendant populations in the Americas.
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| 14. |
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| 15. |
- Gergei, Ingrid, et al.
(författare)
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GWAS META-analysis followed by MENDELIAN randomisation revealed potential control mechanisms for circulating α-klotho levels.
- 2022
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 31:5, s. 792-802
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Tidskriftsartikel (refereegranskat)abstract
- The protein α-Klotho acts as transmembrane the co-receptor for fibroblast growth factor 23 (FGF-23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a GWAS meta-analysis followed by Mendelian randomisation (MR) of circulating α-Klotho levels.Plasma α-Klotho levels were measured by ELISA in the LURIC and ALSPAC (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts.Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (p<5×10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained >9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF-23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes, followed by targeted MR suggested causal effects of liability of Crohn's disease risk [IVW beta=0.059 (95% CI 0.026, 0.093)] and low-density lipoprotein cholesterol (LDL-C) levels [-0.198, (-0.332, -0.063)] on α-Klotho.Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively.
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| 16. |
- Hollfelder, Nina, et al.
(författare)
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The deep population history in Africa
- 2021
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 30:R1, s. R2-R10
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Forskningsöversikt (refereegranskat)abstract
- Africa is the continent with the greatest genetic diversity among humans and the level of diversity is further enhanced by incorporating non-majority groups, which are often understudied. Many of today's minority populations historically practiced foraging lifestyles, which were the only subsistence strategies prior to the rise of agriculture and pastoralism, but only a few groups practicing these strategies remain today. Genomic investigations of Holocene human remains excavated across the African continent show that the genetic landscape was vastly different compared to today's genetic landscape and that many groups that today are population isolate inhabited larger regions in the past. It is becoming clear that there are periods of isolation among groups and geographic areas, but also genetic contact over large distances throughout human history in Africa. Genomic information from minority populations and from prehistoric remains provide an invaluable source of information on the human past, in particular deep human population history, as Holocene large-scale population movements obscure past patterns of population structure. Here we revisit questions on the nature and time of the radiation of early humans in Africa, the extent of gene-flow among human populations as well as introgression from archaic and extinct lineages on the continent.
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| 17. |
- Howard, DM, et al.
(författare)
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Methylome-wide association study of early life stressors and adult mental health
- 2022
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 31:4, s. 651-664
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Tidskriftsartikel (refereegranskat)abstract
- The environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data were assayed at 713 522 CpG sites from 9537 participants of the Generation Scotland: Scottish Family Health Study, a family-based cohort with extensive genetic, medical, family history and lifestyle information. Methylome-wide association studies of eight early life environment phenotypes and two adult mental health phenotypes (major depressive disorder and brief resilience scale) were conducted using DNA methylation data collected from adult whole blood samples. Two genes involved with different developmental pathways (PRICKLE2, Prickle Planar Cell Polarity Protein 2 and ABI1, Abl-Interactor-1) were annotated to CpG sites associated with preterm birth (P < 1.27 × 10−9). A further two genes important to the development of sensory pathways (SOBP, Sine Oculis Binding Protein Homolog and RPGRIP1, Retinitis Pigmentosa GTPase Regulator Interacting Protein) were annotated to sites associated with low birth weight (P < 4.35 × 10−8). The examination of methylation profile scores and genes and gene-sets annotated from associated CpGs sites found no evidence of overlap between the early life environment and mental health conditions. Birth date was associated with a significant difference in estimated lymphocyte and neutrophil counts. Previous studies have shown that early life environments influence the risk of developing mental health disorders later in life; however, this study found no evidence that this is mediated by stable changes to the methylome detectable in peripheral blood.
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| 18. |
- Juodakis, Julius, et al.
(författare)
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Time-varying effects are common in genetic control of gestational duration
- 2023
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Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 32:14, s. 2399-2407
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Tidskriftsartikel (refereegranskat)abstract
- Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent - gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31 000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy 'clock'. We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new fetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm, periods and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant and should help design further experimental studies.
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| 19. |
- Jäger, Susanne, et al.
(författare)
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Blood copper and risk of cardiometabolic diseases : a Mendelian randomization study
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 31:5, s. 783-791
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Tidskriftsartikel (refereegranskat)abstract
- Observational evidence links higher blood levels of copper with higher risk of cardiovascular diseases. However, whether those associations reflect causal links or can be attributed to confounding is still not fully clear. We investigated causal effects of copper on the risk of cardiometabolic endpoints (stroke, coronary artery disease [CAD] and type 2 diabetes) and cardiometabolic risk factors in two-sample Mendelian randomization (MR) studies. The selection of genetic instruments for blood copper levels relied on meta-analysis of genome-wide association studies in three independent studies (European Prospective Investigation into Cancer and Nutrition-Potsdam study, Prospective investigation of the Vasculature in Uppsala Seniors study, Queensland Institute of Medical Research studies). For the selected instruments, outcome associations were drawn from large public genetic consortia on the respective disease endpoints (MEGASTROKE, Cardiogram, DIAGRAM) and cardiometabolic risk factors. MR results indicate an inverse association for genetically higher copper levels with risk of CAD (odds ratio [95% confidence interval] = 0.92 [0.86-0.99], P = 0.022) and systolic blood pressure (beta [standard error (SE)] = -0.238 [0.121]; P = 0.049). Multivariable MR incorporating copper and systolic blood pressure into one model suggested systolic blood pressure as mediating factor between copper and CAD risk. In contrast to previous observational evidence establishing higher blood copper levels as risk-increasing factor for cardiometabolic diseases, this study suggests that higher levels of genetically predicted copper might play a protective role for the development of CAD and systolic blood pressure.
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| 20. |
- Kalamajski, Sebastian, et al.
(författare)
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Genomic editing of metformin efficacy-associated genetic variants in SLC47A1 does not alter SLC47A1 expression
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 31:4, s. 491-498
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Tidskriftsartikel (refereegranskat)abstract
- Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.
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| 21. |
- Khosrowabadi, Elham, et al.
(författare)
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Loss of NDST1 N-sulfotransferase activity is associated with autosomal recessive intellectual disability
- 2024
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 33:6, s. 520-529
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Tidskriftsartikel (refereegranskat)abstract
- Intellectual Disability (ID) is the major cause of handicap, affecting nearly 3% of the general population, and is highly genetically heterogenous with more than a thousand genes involved. Exome sequencing performed in two independent families identified the same missense variant, p.(Gly611Ser), in the NDST1 (N-deacetylase/N-sulfotransferase member 1) gene. This variant had been previously found in ID patients of two other families but has never been functionally characterized. The NDST1 gene encodes a bifunctional enzyme that catalyzes both N-deacetylation and N-sulfation of N-acetyl-glucosamine residues during heparan sulfate (HS) biosynthesis. This step is essential because it influences the downstream enzymatic modifications and thereby determines the overall structure and sulfation degree of the HS polysaccharide chain. To discriminate between a rare polymorphism and a pathogenic variant, we compared the enzymatic properties of wild-type and mutant NDST1 proteins. We found that the p.(Gly611Ser) variant results in a complete loss of N-sulfotransferase activity while the N-deacetylase activity is retained. NDST1 shows the highest and the most homogeneous expression in the human cerebral structures compared to the other members of the NDST gene family. These results indicate that a loss of NDST1 N-sulfation activity is associated with impaired cognitive functions.
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| 22. |
- Kleinstern, G, et al.
(författare)
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Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways
- 2020
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 29:1, s. 70-79
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Tidskriftsartikel (refereegranskat)abstract
- We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
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| 23. |
- Kolterud, A, et al.
(författare)
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Molecular subclass of uterine fibroids predicts tumor shrinkage in response to ulipristal acetate
- 2023
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 32:7, s. 1063-1071
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Tidskriftsartikel (refereegranskat)abstract
- Precision medicine carries great potential for management of all tumor types. The aim of this retrospective study was to investigate if the two most common genetically distinct uterine fibroid subclasses, driven by aberrations in MED12 and HMGA2 genes, respectively, influence response to treatment with the progesterone receptor modulator ulipristal acetate. Changes in diameter and mutation status were derived for 101 uterine fibroids surgically removed after ulipristal acetate treatment. A significant difference in treatment response between the two major subclasses was detected. MED12 mutant fibroids had 4.4 times higher odds of shrinking in response to ulipristal acetate treatment as compared to HMGA2 driven fibroids (95% confidence interval 1.37–13.9; P = 0.013), and in a multivariate analysis molecular subclassification was an independent predictive factor. Compatible with this finding, gene expression and DNA methylation analyses revealed subclass specific differences in progesterone receptor signaling. The work provides a proof-of-principle that uterine fibroid treatment response is influenced by molecular subclass and that the genetic subclasses should be taken into account when evaluating current and future uterine fibroid therapies.
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| 24. |
- Li, Yafang, et al.
(författare)
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Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:16, s. 2831-2843
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Tidskriftsartikel (refereegranskat)abstract
- Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.
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| 25. |
- Liu, Z. G., et al.
(författare)
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Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features
- 2023
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Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 32:20, s. 2981-2995
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Tidskriftsartikel (refereegranskat)abstract
- Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.
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