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- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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- Kupers, LK, et al.
(författare)
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Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1893-
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Tidskriftsartikel (refereegranskat)abstract
- Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10−7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10−74) and BMI in pregnancy (3/914, p = 1.13x10−3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
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- Bethlehem, RAI, et al.
(författare)
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Brain charts for the human lifespan
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 604:7906, s. 525-
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Tidskriftsartikel (refereegranskat)abstract
- Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data (http://www.brainchart.io/). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
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- Hagg, S, et al.
(författare)
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Short telomere length is associated with impaired cognitive performance in European ancestry cohorts
- 2017
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:4, s. e1100-
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Tidskriftsartikel (refereegranskat)abstract
- The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=−0.053; 95% CI: −0.087, −0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10−5), whereas carriers performed better in STROOP (β=−0.074; 95% CI: −0.140, −0.009; P=0.03). Causal associations were found for STROOP only (β=−0.598 per s.d.-increase of TL; 95% CI: −1.125, −0.072; P=0.026), with a larger effect in ɛ4-carriers (β=−0.699; 95% CI: −1.330, −0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.
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- Stokowy, T, et al.
(författare)
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Genetic variation in 117 myelination-related genes in schizophrenia: Replication of association to lipid biosynthesis genes
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 6915-
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a serious psychotic disorder with high heritability. Several common genetic variants, rare copy number variants and ultra-rare gene-disrupting mutations have been linked to disease susceptibility, but there is still a large gap between the estimated and explained heritability. Since several studies have indicated brain myelination abnormalities in schizophrenia, we aimed to examine whether variants in myelination-related genes could be associated with risk for schizophrenia. We established a set of 117 myelination genes by database searches and manual curation. We used a combination of GWAS (SCZ_N = 35,476; CTRL_N = 46,839), exome chip (SCZ_N = 269; CTRL_N = 336) and exome sequencing data (SCZ_N = 2,527; CTRL_N = 2,536) from schizophrenia cases and healthy controls to examine common and rare variants. We found that a subset of lipid-related genes was nominally associated with schizophrenia (p = 0.037), but this signal did not survive multiple testing correction (FWER = 0.16) and was mainly driven by the SREBF1 and SREBF2 genes that have already been linked to schizophrenia. Further analysis demonstrated that the lowest nominal p-values were p = 0.0018 for a single common variant (rs8539) and p = 0.012 for burden of rare variants (LRP1 gene), but none of them survived multiple testing correction. Our findings suggest that variation in myelination-related genes is not a major risk factor for schizophrenia.
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- Wesseldijk, LW, et al.
(författare)
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Notes from Beethoven's genome
- 2024
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Ingår i: Current biology : CB. - 1879-0445. ; 34:6, s. R233-R234
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Tidskriftsartikel (refereegranskat)
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