| 1. |
- Boen, Rune, et al.
(författare)
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Beyond the global brain differences : intraindividual variability differences in 1q21.1 distal and 15q11.2 bp1-bp2 deletion carriers
- 2024
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Ingår i: Biological Psychiatry. - 0006-3223 .- 1873-2402. ; 95:2, s. 147-160
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Tidskriftsartikel (refereegranskat)abstract
- Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference.Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness.Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
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| 2. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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| 3. |
- Sonderby, Ida E., et al.
(författare)
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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
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Tidskriftsartikel (refereegranskat)abstract
- Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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| 4. |
- Sønderby, Ida E., et al.
(författare)
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1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
- 2021
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Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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| 5. |
- van der Meer, Dennis, et al.
(författare)
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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
- 2020
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 77:4, s. 420-430
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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| 6. |
- Wong, Sandy, et al.
(författare)
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Associations between daily ambient temperature and sedentary time among children 4-6 years old in Mexico City
- 2020
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Background Sedentary behavior is a worldwide public health concern. There is consistent and growing evidence linking sedentary behavior to mortality and morbidity. Early monitoring and assessment of environmental factors associated with sedentary behaviors at a young age are important initial steps for understanding children's sedentary time and identifying pertinent interventions. Objective This study examines the association between daily temperature (maximum, mean, minimum, and diurnal variation) and all-day sedentary time among 4-6 year old children in Mexico City (n = 559) from the year 2013 to 2015. Methods We developed a spatiotemporally resolved hybrid satellite-based land use regression temperature model and calculated percent daily sedentary time from aggregating 10-second epoch vertical counts captured by accelerometers that participants wore for one week. We modeled generalized additive models (GAMs), one for each temperature type as a covariate (maximum, mean, minimum, and diurnal variation). All GAMs included percent all-day sedentary time as the outcome and participant-level random intercepts to account for repeated measures of sedentary time. Our models were adjusted for demographic factors and environmental exposures. Results Daily maximum temperature, mean temperature, and diurnal variation have significant negative linear relationships with all-day sedentary time (p<0.01). There is no significant association between daily minimum temperature and all-day sedentary time. Children have on average 0.26% less daily sedentary time (approximately 2.2 minutes) for each 1 degrees C increase in ambient maximum temperature (range 7.1-30.2 degrees C), 0.27% less daily sedentary time (approximately 2.3 minutes) for each 1 degrees C increase in ambient mean temperature (range 4.3-22.2 degrees C), and 0.23% less daily sedentary time (approximately 2.0 minutes) for each 1 degrees C increase in diurnal variation (range 3.0-21.6 degrees C). Conclusions These results are contrary to our hypothesis in which we expected a curvilinear relationship between temperature (maximum, mean, minimum, and diurnal variation) and sedentary time. Our findings suggest that temperature is an important environmental factor that influences children's sedentary behavior.
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| 7. |
- Wu, Haotian, et al.
(författare)
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Association of ambient PM2.5 exposure with maternal bone strength in pregnant women from Mexico City : a longitudinal cohort study
- 2020
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Ingår i: The Lancet Planetary Health. - 2542-5196. ; 4:11, s. E530-E537
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Tidskriftsartikel (refereegranskat)abstract
- Background Pregnancy is associated with deteriorations in maternal bone strength and heightened susceptibility to bone fractures. We aimed to investigate whether ambient particulate matter (PM)(2.5) concentrations were associated with bone strength during pregnancy. Methods In this longitudinal cohort study, we analysed longitudinal data from women participating in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort in Mexico City, Mexico. Eligible women were aged 18 years or older, at less than 20 weeks' gestation at the time of recruitment, planning to stay in Mexico City for the next 3 years, without heart or kidney disease, did not use steroids or anti-epileptic drugs, were not daily consumers of alcohol, and had access to a telephone. Daily ambient PM2.5 concentrations were estimated from a spatio-temporal model that was based on the individual's address. Trabecular bone strength was measured using quantitative ultrasound from the radius of the middle finger and cortical bone strength from the proximal phalanx of the middle finger, during the second trimester, third trimester, and 1 and 6 months post partum. Bone strength T scores were modelled with PM2.5 concentrations using linear mixed models and distributed lag models. Findings Adjusting for multiple exposure windows, each 10 mu g/m(3) increase in PM2.5 exposure concentrations in the first trimester was associated with a 0.18 SD decrease (95% CI -0.35 to -0.01; p=0.033) in ultrasound speed-of-sound (SOS) T score of trabecular bone strength from the second trimester until 6 months post partum. Similarly, each 10 mu g/m(3) increase in third trimester PM2.5 exposure was associated with a 0.18 SD decrease (-0.36 to -0.01; p=0.044) in the SOS T score of trabecular bone strength from the third trimester until 6 months post partum. PM2.5 exposure in the first month post partum was associated with a 0.20 SD decline (-0.39 to -0.01; p=0.043) in cortical bone strength until 6 months post partum. Interpretation Ambient PM2.5 exposure during and after pregnancy was associated with diminished trabecular and cortical bone strength. Early pregnancy PM2.5 exposure was associated with a greater decline in bone strength later during pregnancy. Late pregnancy and early post-partum exposures adversely affected the post-partum bone strength recovery. Technological and policy solutions to reduce PM2.5 pollution could improve public health by reducing bone fracture risk.
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