Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis

Common diseases such as endometriosis (ED), Alzheimer's disease (AD) and multiple sclerosis (MS) account for a significant proportion of the health care burden in many countries. Genome-wide association studies (GWASs) for these diseases have identified a number of individual genetic variants contributing to the risk of those diseases. However, the effect size for most variants is small and collectively the known variants explain only a small proportion of the estimated heritability. We used a linear mixed model to fit all single nucleotide polymorphisms (SNPs) simultaneously, and estimated genetic variances on the liability scale using SNPs from GWASs in unrelated individuals for these three diseases. For each of the three diseases, case and control samples were not all genotyped in the same laboratory. We demonstrate that a careful analysis can obtain robust estimates, but also that insufficient quality control (QC) of SNPs can lead to spurious results and that too stringent QC is likely to remove real genetic signals. Our estimates show that common SNPs on commercially available genotyping chips capture significant variation contributing to liability for all three diseases. The estimated proportion of total variation tagged by all SNPs was 0.26 (SE 0.04) for ED, 0.24 (SE 0.03) for AD and 0.30 (SE 0.03) for MS. Further, we partitioned the genetic variance explained into five categories by a minor allele frequency (MAF), by chromosomes and gene annotation. We provide strong evidence that a substantial proportion of variation in liability is explained by common SNPs, and thereby give insights into the genetic architecture of the diseases.

Isolation and Estimation of Cytokinins and Cytokinin-Containing Transfer RNAs from Cucumis

N6-({Delta}2-Isopentenyl) adenosine antibodies were used for the isolation of free cytokinins and cytokinin-containing tRNAs from parts of Cucumis sativus L. var. Guntur seedlings and for the estimation of cytokinins in them. Immobilized N6-({Delta}2-isopentenyl) adenosine antibodies retained tRNAs containing N6-({Delta}2-isopentenyl) adenosine and N6-(4-hydroxy-3-methylbut-2-enyl) adenosine with equal efficiencies. There were at least five cytokinins in the free form in cucumber seedlings. N6-(4-Hydroxy-3-methylbut-2-enyl) adenosine, N6-({Delta}2-isopentenyl) adenosine, and N6-({Delta}2-isopentenyl) adenine were present at least to the extent of 80, 23, and 9 nanograms, respectively, in the cotyledons and 40, 6, and 3 nanograms, respectively, in the decotyledonated seedlings per gram of tissue. Only two cytokinins were found in the tRNAs of cucumber cotyledons, namely N6-({Delta}2-isopentenyl) adenosine and N6-(4-hydroxy-3-methylbut-2-enyl) adenosine in amounts of 12 and 318 nanograms, respectively, per gram of tissue. Immunoaffinity chromatographic analysis of radiolabeled aminoacyl tRNAs from cucumber cotyledons showed that tRNAPhe and tRNATyr contained cytokinins whereas tRNAAla did not.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 x 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-kappaB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Loci affecting gamma-glutamyl transferase in adults and adolescents show age x SNP interaction and cardiometabolic disease associations

Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 x 10(-8); rs944002 in C14orf73 on chromosome 14, P = 4.7 x 10(-13); rs340005 in RORA on chromosome 15, P = 2.4 x 10(-8)), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P(HET) = 5.6 x 10(-12) at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.

Reproduction of portrait of Kurt Fritz Rosenberg at age four; Hamburg.

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Statistical analysis of the associations of hereditary factors with the risk of Type 1 diabetes and Diabetic Nephropathy based on the familial data collected through ascertaiment from population-based registers

In genetic epidemiology, population-based disease registries are commonly used to collect genotype or other risk factor information concerning affected subjects and their relatives. This work presents two new approaches for the statistical inference of ascertained data: a conditional and full likelihood approaches for the disease with variable age at onset phenotype using familial data obtained from population-based registry of incident cases. The aim is to obtain statistically reliable estimates of the general population parameters. The statistical analysis of familial data with variable age at onset becomes more complicated when some of the study subjects are non-susceptible, that is to say these subjects never get the disease. A statistical model for a variable age at onset with long-term survivors is proposed for studies of familial aggregation, using latent variable approach, as well as for prospective studies of genetic association studies with candidate genes. In addition, we explore the possibility of a genetic explanation of the observed increase in the incidence of Type 1 diabetes (T1D) in Finland in recent decades and the hypothesis of non-Mendelian transmission of T1D associated genes. Both classical and Bayesian statistical inference were used in the modelling and estimation. Despite the fact that this work contains five studies with different statistical models, they all concern data obtained from nationwide registries of T1D and genetics of T1D. In the analyses of T1D data, non-Mendelian transmission of T1D susceptibility alleles was not observed. In addition, non-Mendelian transmission of T1D susceptibility genes did not make a plausible explanation for the increase in T1D incidence in Finland. Instead, the Human Leucocyte Antigen associations with T1D were confirmed in the population-based analysis, which combines T1D registry information, reference sample of healthy subjects and birth cohort information of the Finnish population. Finally, a substantial familial variation in the susceptibility of T1D nephropathy was observed. The presented studies show the benefits of sophisticated statistical modelling to explore risk factors for complex diseases.

Stroke and coronary heart disease in relation to hyperglycemia gender and age

This study was carried out to compare the fasting plasma glucose (FPG) and 2-h plasma glucose (2-h PG) criteria for diabetes with regard to their relation to stroke mortality and the incidence of ischemic and hemorrhagic stroke. In addition, the age-and gender difference in the incidence of coronary heart disease (CHD) and stroke and their relation with known cardiovascular disease risk factors and diabetes mellitus was examined. The study was a sub-data analysis of the Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study including 25 181 individuals, 11 844 (47%) men and 13 345 (53%) women aged 25 to 90 years, from 14 European cohorts. In individuals without a history of diabetes elevated 2-h post-challenge glucose was a better predictor of stroke mortality than elevated fasting glucose in men, whereas the latter was better than the former in women. Elevated FPG and 2-h PG levels were associated with an increased risk of ischemic stroke incidence. 2-h PG contributed to the risk more strongly than FPG. No relationship between hyperglycemia and the risk of hemorrhagic stroke was found. The risk of CHD and ischemic stroke incidence increased with age in both genders, but was higher in all age groups in men than in women. The gender difference was, however, more marked for CHD than for ischemic stroke. Age, smoking and diabetes contributed to the development of both CHD and ischemic stroke. Elevated cholesterol levels predicted CHD only, whereas elevated blood pressure was a risk predictor for the incidence of ischemic stroke. The CHD and ischemic stroke risk was higher in men than in women with and without diabetes, however, the gender difference diminished for CHD but enlarged for ischemic stroke in diabetic individuals. The known risk factors including diabetes contributed differently to the risk of CHD and ischemic stroke in women and in men. Hyperglycemia defined by FPG or 2-h PG increases the risk of ischemic stroke in individuals without diabetes. FPG better predicts stroke mortality in women and 2-h PG in men. The risk of acute CHD and ischemic stroke is higher in men than in women in all ages, but such gender difference is more marked for CHD than for ischemic stroke. CHD risk is higher in men than in women, but the difference is reduced in diabetic population. Diabetes, however, increases stroke risk more in men than in women in all ages.

CSSI-PRO: a method for secondary structure type editing, assignment and estimation in proteins using linear combination of backbone chemical shifts

Estimation of secondary structure in polypeptides is important for studying their structure, folding and dynamics. In NMR spectroscopy, such information is generally obtained after sequence specific resonance assignments are completed. We present here a new methodology for assignment of secondary structure type to spin systems in proteins directly from NMR spectra, without prior knowledge of resonance assignments. The methodology, named Combination of Shifts for Secondary Structure Identification in Proteins (CSSI-PRO), involves detection of specific linear combination of backbone H-1(alpha) and C-13' chemical shifts in a two-dimensional (2D) NMR experiment based on G-matrix Fourier transform (GFT) NMR spectroscopy. Such linear combinations of shifts facilitate editing of residues belonging to alpha-helical/beta-strand regions into distinct spectral regions nearly independent of the amino acid type, thereby allowing the estimation of overall secondary structure content of the protein. Comparison of the predicted secondary structure content with those estimated based on their respective 3D structures and/or the method of Chemical Shift Index for 237 proteins gives a correlation of more than 90% and an overall rmsd of 7.0%, which is comparable to other biophysical techniques used for structural characterization of proteins. Taken together, this methodology has a wide range of applications in NMR spectroscopy such as rapid protein structure determination, monitoring conformational changes in protein-folding/ligand-binding studies and automated resonance assignment.

Studio portrait of Benno Strauss in military uniform after being drafted to fight on the front during World War I at the age of thirty-nine.

Father of Herbert Strauss

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10−61) than father–offspring correlation (r=0.33; P-value=7.01 × 10−5), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10−5). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10−30) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10−23) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10−10). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.

Improving the estimation of probability of bidder participation in procurement auctions

Anticipating the number and identity of bidders has significant influence in many theoretical results of the auction itself and bidders’ bidding behaviour. This is because when a bidder knows in advance which specific bidders are likely competitors, this knowledge gives a company a head start when setting the bid price. However, despite these competitive implications, most previous studies have focused almost entirely on forecasting the number of bidders and only a few authors have dealt with the identity dimension qualitatively. Using a case study with immediate real-life applications, this paper develops a method for estimating every potential bidder’s probability of participating in a future auction as a function of the tender economic size removing the bias caused by the contract size opportunities distribution. This way, a bidder or auctioner will be able to estimate the likelihood of a specific group of key, previously identified bidders in a future tender.

Age-related changes in hepatic function: An update on implications for drug therapy

The accumulation of deficits with increasing age results in a decline in the functional capacity of multiple organs and systems. These changes can have a significant influence on the pharmacokinetics and pharmacodynamics of prescribed drugs. Although alterations in body composition and worsening renal clearance are important considerations, for most drugs the liver has the greatest effect on metabolism. Age-related change in hepatic function thereby causes much of the variability in older people’s responses to medication. In this review, we propose that a decline in the ability of the liver to inactivate toxins may contribute to a proinflammatory state in which frailty can develop. Since inflammation also downregulates drug metabolism, medication prescribed to frail older people in accordance with disease-specific guidelines may undergo reduced systemic clearance, leading to adverse drug reactions, further functional decline and increasing polypharmacy, exacerbating rather than ameliorating frailty status. We also describe how increasing chronological age and frailty status impact liver size, blood flow and protein binding and enzymes of drug metabolism. This is used to contextualise our discussion of appropriate prescribing practices. For example, while the general axiom of ‘start low, go slow’ should underpin the initiation of medication (titrating to a defined therapeutic goal), it is important to consider whether drug clearance is flow or capacity-limited. By summarising the effect of age-related changes in hepatic function on medications commonly used in older people, we aim to provide a guide that will have high clinical utility for practising geriatricians.

Reproduction of painted portrait of Marcus Elias Marcus, age 76. Portraits Men

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Telomere dynamics in the Sydney rock oyster (Saccostrea glomerata): an investigation into the effects of age, tissue type, location and time of sampling.

Telomere length has been purported as a biomarker for age and could offer a non-lethal method for determining the age of wild-caught individuals. Molluscs, including oysters and abalone, are the basis of important fisheries globally and have been problematic to accurately age. To determine whether telomere length could provide an alternative means of ageing molluscs, we evaluated the relationship between telomere length and age using the commercially important Sydney rock oyster (Saccostrea glomerata). Telomere lengths were estimated from tissues of known age individuals from different age classes, locations and at different sampling times. Telomere length tended to decrease with age only in young oysters less than 18 months old, but no decrease was observed in older oysters aged 2-4 years. Regional and temporal differences in telomere attrition rates were also observed. The relationship between telomere length and age was weak, however, with individuals of identical age varying significantly in their telomere length making it an imprecise age biomarker in oysters.