| 1. |
- Nikpay, Majid, et al.
(författare)
-
A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
- 2015
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:10, s. 1121-1121
-
Tidskriftsartikel (refereegranskat)abstract
- Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
|
|
| 2. |
- Middeldorp, Christel M., et al.
(författare)
-
The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
- 2019
-
Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 279-300
-
Tidskriftsartikel (refereegranskat)abstract
- The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
|
|
| 3. |
- Vogelezang, Suzanne, et al.
(författare)
-
Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
- 2020
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:10
-
Tidskriftsartikel (refereegranskat)abstract
- The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
|
|
| 4. |
- Kok, Eloise H., et al.
(författare)
-
Beer Drinking Associates with Lower Burden of Amyloid Beta Aggregation in the Brain : Helsinki Sudden Death Series
- 2016
-
Ingår i: Alcoholism. - : Wiley. - 0145-6008 .- 1530-0277. ; 40:7, s. 1473-1478
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundControversy surrounds the effect of alcohol consumption on the development of dementia and cognitive impairment. We investigated the association between consumption of different alcoholic beverages and -amyloid (A) aggregation in the brain, 1 of the neuropathological lesions of Alzheimer's disease. MethodsIn total, 125 males of the Helsinki Sudden Death autopsy Series were included with an age range at death 35 to 70years. The consumption of alcohol, A aggregation in the brain, and Apolipoprotein E (APOE) genotype were assessed. Relatives answered a questionnaire to gather alcohol consumption history, and A was visualized by implementing immunohistochemical staining of brain sections. A immunoreactivity (IR) was assessed in a dichotomized (yes/no) fashion and as a stained area fraction (%). APOE genotype was assessed in DNA extracted from paraffin-embedded cardiac muscle samples. ResultsIncreased age (p=0.001; odds ratio [OR]=1.09, confidence interval [CI]=1.04 to 1.15) was associated with higher prevalence of A-IR. Beer drinking decreased (p=0.024; OR=0.35, CI=0.14 to 0.87) the prevalence of A-IR and was associated with a significantly lower extent of A-IR (p=0.022). The amount of alcohol consumed was not linked with A aggregation and neither was spirit nor wine consumption. ConclusionsBeer consumption may protect against A aggregation in brain. Further studies are necessary to fully understand the effects of alcohol on A pathology seen in brain tissue.
|
|
| 5. |
- Olsson, Jan, et al.
(författare)
-
HSV presence in brains of individuals without dementia : the TASTY brain series
- 2016
-
Ingår i: Disease Models and Mechanisms. - : The Company of Biologists. - 1754-8403 .- 1754-8411. ; 9:11, s. 1349-1355
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus (HSV) type 1 affects a majority of the population and recent evidence suggests involvement in Alzheimer's disease aetiology. We investigated the prevalence of HSV type 1 and 2 in the Tampere Autopsy Study (TASTY) brain samples using PCR and sero-positivity in plasma, and associations with Alzheimer's disease neuropathology. HSV was shown to be present in human brain tissue in 11/584 (1.9%) of samples in the TASTY cohort, of which six had Alzheimer's disease neuropathological amyloid beta (A beta) aggregations. Additionally, serological data revealed 86% of serum samples tested were IgG-positive for HSV. In conclusion, we report epidemiological evidence of the presence of HSV in brain tissue free from encephalitis symptoms in a cohort most closely representing the general population (a minimum prevalence of 1.9%). Whereas 6/11 samples with HSV DNA in the brain tissue had A beta aggregations, most of those with A beta aggregations did not have HSV present in the brain tissue.
|
|
| 6. |
- Pohjoismäki, Jaakko L O, et al.
(författare)
-
Postnatal cardiomyocyte growth and mitochondrial reorganization cause multiple changes in the proteome of human cardiomyocytes.
- 2013
-
Ingår i: Molecular Biosystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 9:6
-
Tidskriftsartikel (refereegranskat)abstract
- Fetal (fCM) and adult cardiomyocytes (aCM) significantly differ from each other both by structure and biochemical properties. aCM own a higher mitochondrial mass compared to fCM due to increased energy demand and show a greater density and higher degree of structural organization of myofibrils. The energy metabolism in aCM relies virtually completely on β-oxidation of fatty acids while fCM use carbohydrates. Rewinding of the aCM phenotype (de-differentiation) arises frequently in diseased hearts spurring questions about its functional relevance and the extent of de-differentiation. Yet, surprisingly little is known about the changes in the human proteome occurring during maturation of fCM to aCM. Here, we examined differences between human fetal and adult hearts resulting in the quantification of 3500 proteins. Moreover, we analyzed mitochondrial proteomes from both stages to obtain more detailed insight into underlying biochemical differences. We found that the majority of changes between fCM and aCM were attributed to growth and maturation of cardiomyocytes. As expected, adult hearts showed higher mitochondrial mass and expressed increased levels of proteins involved in energy metabolism but relatively lower copy numbers of mitochondrial DNA (mtDNA) per total cell volume. We uncovered that the TFAM/mtDNA ratio was kept constant during postnatal development despite a significant increase of mitochondrial protein per mtDNA in adult mitochondria, which revises previous concepts.
|
|
