Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and ...early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10⁻⁸) near FTO (P = 3.72 × 10⁻²³), TMEM18 (P = 3.24 × 10⁻¹⁷), MC4R (P = 4.41 × 10⁻¹⁷), TNNI3K (P = 4.32 × 10⁻¹¹), SEC16B (P = 6.24 × 10⁻⁹), GNPDA2 (P = 1.11 × 10⁻⁸) and POMC (P = 4.94 × 10⁻⁸) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10⁻⁵ after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.
The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of ...studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of genetic risk prediction studies (the GRIPS statement), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published at http://www.plosmedicine.org.
Persons with Down syndrome show an altered immune response and an increased susceptibility to Alzheimer's disease. In a prospective study, we examined whether the plasma neopterin level, a marker for ...cell-mediated immune activation and inflammation, is associated with an increased risk of dementia in persons with Down syndrome. Plasma concentrations of neopterin were determined in a population-based study of 394 persons with Down syndrome, who were screened annually for dementia. We used Cox proportional hazards model to determine risk of dementia. Demented persons with Down syndrome have a significantly (
p
=
0.05) higher plasma neopterin concentration than the non-demented. In the non-demented without autoimmune disorders, in those with a plasma level of neopterin above median, the risk to develop dementia increased to 1.83 (95% confidence interval: 1.04–3.20). High plasma neopterin level is an independent determinant of the risk of dementia in persons with Down syndrome.
Background
There is an important interplay between the gut microbiome and brain, commonly known as the gut‐brain‐axis. Several studies addressed the role of the microbiome in neurologic diseases. ...Here, we studied the role of microbiota in cognitive function, neurovascular changes, and neurodegenerative changes in the general population.
Method
In the population‐based Rotterdam Study, we studied the association between microbial taxa and cognitive function in 1,184 participants and the association between microbial taxa and neurovascular and neurodegenerative traits, measured on brain magnetic resonance imaging, in 1,241 participants. Gut microbiota were profiled using 16 s rRNA gene sequencing. We used linear regression analysis to study these associations and adjusted for major confounders, i.e., age, sex, technical covariates, medication use, alcohol, smoking, body mass index, and hypertension.
Result
We found that the genus Clostridium sensu stricto 1 showed a higher abundance in participants with better cognitive function (beta(β)(standard error(SE)) 0.023(0.01), p = 3.22 × 10−2), larger global brain volume (β(SE) 0.0019(0.0006), p = 1.83 × 10−3), less white matter hyperintensities (β(SE) ‐0.024(0.007), p = 5.38 × 10−4), and smaller lateral ventricular volume (β(SE) ‐0.013(0.005), p = 1.81 × 10−2). The family Clostridiaceae 1 also showed a higher abundance in these traits, with the same direction of effect and very similar effect estimates. The class Clostridia, order Clostridiales, family Christensenellaceae, and genus Christensenellaceae R7 group showed a higher abundance in better cognition. Of note is that the agreement of our findings with those of studies of Alzheimer’s disease is high.
Conclusion
Clostridium shows a higher abundance in less neurovascular changes, in less neurodegenerative changes, and in better cognition. We find that different microbiota are associated to neurovascular and neurodegenerative pathology.
Abstract
Background
There is an important interplay between the gut microbiome and brain, commonly known as the gut‐brain‐axis. Several studies addressed the role of the microbiome in neurologic ...diseases. Here, we studied the role of microbiota in cognitive function, neurovascular changes, and neurodegenerative changes in the general population.
Method
In the population‐based Rotterdam Study, we studied the association between microbial taxa and cognitive function in 1,184 participants and the association between microbial taxa and neurovascular and neurodegenerative traits, measured on brain magnetic resonance imaging, in 1,241 participants. Gut microbiota were profiled using 16 s rRNA gene sequencing. We used linear regression analysis to study these associations and adjusted for major confounders, i.e., age, sex, technical covariates, medication use, alcohol, smoking, body mass index, and hypertension.
Result
We found that the genus
Clostridium sensu stricto 1
showed a higher abundance in participants with better cognitive function (beta(β)(standard error(SE)) 0.023(0.01),
p
= 3.22 × 10
−2
), larger global brain volume (β(SE) 0.0019(0.0006),
p
= 1.83 × 10
−3
), less white matter hyperintensities (β(SE) ‐0.024(0.007),
p
= 5.38 × 10
−4
), and smaller lateral ventricular volume (β(SE) ‐0.013(0.005),
p
= 1.81 × 10
−2
). The family
Clostridiaceae 1
also showed a higher abundance in these traits, with the same direction of effect and very similar effect estimates. The class
Clostridia
, order
Clostridiales
, family
Christensenellaceae
, and genus
Christensenellaceae R7 group
showed a higher abundance in better cognition. Of note is that the agreement of our findings with those of studies of Alzheimer’s disease is high.
Conclusion
Clostridium
shows a higher abundance in less neurovascular changes, in less neurodegenerative changes, and in better cognition. We find that different microbiota are associated to neurovascular and neurodegenerative pathology.
An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to ...insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy.
This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort.
Minor allele frequency did not differ significantly (p = 0.47) between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort.
We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective To investigate the relationship between the apolipoprotein E (APOE) gene and the risk of mortality in normal weight, overweight and obese individuals. Methods and Results In a population- ...based study of 7,983 individuals aged 55 years and older, we compared the risks of all-cause and coronary heart disease (CHD) mortality by APOE genotype, both overall and in subgroups defined by body mass index (BMI). We found significant evidence for interaction between APOE and BMI in relation to total cholesterol (p = 0.04) and HDL cholesterol (p < 0.001). Overall, APOE*2 carriers showed a decreased risk of all-cause mortality. Analyses within BMI strata showed a beneficial effect of APOE*2 only in normal weight persons (adjusted hazard ratio (HR) 0.795% CI 0.5-0.9). APOE*2 was not associated with a lower risk of all-cause mortality in overweight or obese persons. The effect of APOE*2 in normal weight individuals tended to be due to the risk of CHD mortality (adjusted HR 0.5 95% CI 0.2-1.2). Conclusion The APOE*2 allele confers a lower risk of all-cause mortality only to normal weight individuals.
Background:
Smoking-associated DNA methylation levels identified through epigenome-wide association studies (EWASs) are generally ascribed to smoking-reactive mechanisms, but the contribution of a ...shared genetic predisposition to smoking and DNA methylation levels is typically not accounted for.
Methods:
We exploited a strong within-family design, that is, the discordant monozygotic twin design, to study reactiveness of DNA methylation in blood cells to smoking and reversibility of methylation patterns upon quitting smoking. Illumina HumanMethylation450 BeadChip data were available for 769 monozygotic twin pairs (mean age = 36 years, range = 18–78, 70% female), including pairs discordant or concordant for current or former smoking.
Results:
In pairs discordant for current smoking, 13 differentially methylated CpGs were found between current smoking twins and their genetically identical co-twin who never smoked. Top sites include multiple CpGs in
CACNA1D
and
GNG12
, which encode subunits of a calcium voltage-gated channel and G protein, respectively. These proteins interact with the nicotinic acetylcholine receptor, suggesting that methylation levels at these CpGs might be reactive to nicotine exposure. All 13 CpGs have been previously associated with smoking in unrelated individuals and data from monozygotic pairs discordant for former smoking indicated that methylation patterns are to a large extent reversible upon smoking cessation. We further showed that differences in smoking level exposure for monozygotic twins who are both current smokers but differ in the number of cigarettes they smoke are reflected in their DNA methylation profiles.
Conclusions:
In conclusion, by analysing data from monozygotic twins, we robustly demonstrate that DNA methylation level in human blood cells is reactive to cigarette smoking.
Funding:
We acknowledge funding from the National Institute on Drug Abuse grant DA049867, the Netherlands Organization for Scientific Research (NWO): Biobanking and Biomolecular Research Infrastructure (BBMRI-NL, NWO 184.033.111) and the BBRMI-NL-financed BIOS Consortium (NWO 184.021.007), NWO Large Scale infrastructures X-Omics (184.034.019), Genotype/phenotype database for behaviour genetic and genetic epidemiological studies (ZonMw Middelgroot 911-09-032); Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO-Groot 480-15-001/674); the Avera Institute, Sioux Falls (USA), and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995); epigenetic data were generated at the Human Genomics Facility (HuGe-F) at ErasmusMC Rotterdam. Cotinine assaying was sponsored by the Neuroscience Campus Amsterdam. DIB acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635).
The genetic information of people who smoke present distinctive characteristics. In particular, previous research has revealed differences in patterns of DNA methylation, a type of chemical modification that helps cells switch certain genes on or off. However, most of these studies could not establish for sure whether these changes were caused by smoking, predisposed individuals to smoke, or were driven by underlying genetic variation in the DNA sequence itself.
To investigate this question, van Dongen et al. examined DNA methylation data from the blood cells of over 700 pairs of identical twins. These individuals share the exact same genetic information, making it possible to better evaluate the impact of lifestyle on DNA modifications.
The analyses identified differences in methylation at 13 DNA locations in pairs of twins where one was a current smoker and their sibling had never smoked. Two of the genes code for proteins involved in the response to nicotine, the primary addictive chemical in cigarette smoke. The differences were smaller if one of the twins had stopped smoking, suggesting that quitting can help to reverse some of these changes.
These findings confirm that DNA methylation in blood cells is influenced by cigarette smoke, which could help to better understand smoking-associated diseases. They also demonstrate how useful identical twins studies can be to identify methylation changes that are markers of lifestyle.
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