Interactions between chromosomal and nonchromosomal elements reveal missing heritability

The measurement of any nonchromosomal genetic contribution to the heritability of a trait is often confounded by the inability to control both the chromosomal and nonchromosomal information in a population. We have designed a unique system in yeast where we can control both sources of information so that the phenotype of a single chromosomal polymorphism can be measured in the presence of different cytoplasmic elements. With this system, we have shown that both the source of the mitochondrial genome and the presence or absence of a dsRNA virus influence the phenotype of chromosomal variants that affect the growth of yeast. Moreover, by considering this nonchromosomal information that is passed from parent to offspring and by allowing chromosomal and nonchromosomal information to exhibit nonadditive interactions, we are able to account for much of the heritability of growth traits. Taken together, our results highlight the importance of including all sources of heritable information in genetic studies and suggest a possible avenue of attack for finding additional missing heritability.A fundamental problem in genetics is unraveling the link between genotype and phenotype. Ascertaining the heritability of a trait is a key step toward harnessing the predictive capacity of genetic information for human disease risk assessment and therapy (1). Knowledge of all of the elements contributing to heritability would facilitate the establishment of a causal relationship between the information that is passed down from generation to generation and the resulting phenotype. Genome-wide association studies (GWASs) have successfully identified many human polymorphisms that are associated with traits such as height, eye color, or susceptibility to common diseases, but these variants typically explain only a small proportion of the observed heritability of a trait (2, 3).A number of explanations for missing heritability have been suggested (2), including the existence of many weak variants with effects too small to achieve statistical significance (4), interactions between variants that cannot be identified with current studies (5), rare variants that were not identified by GWAS, and epigenetic effects (6–8). The contribution of nonchromosomal information to the missing heritability is rarely considered, despite the fact that there is a long history documenting the effect in many organisms of diverse cytoplasmic elements on phenotype. Recent work on a mouse model of Crohn disease supports a combinatorial model of complex disease traits in which the pathology requires the interaction between a specific mutation in the mouse and a specific strain of virus (9). Another recent study showed strong effects on the plant metabolome stemming from variation in mitochondrial and chloroplast genomes (10). In humans, the importance of nonchromosomal information has been supported by targeted analyses, but these studies have not analyzed its impact on heritability in a well-controlled context (11–13). Such nonchromosomal interactions might help explain why shared mutations in humans do not always produce the same phenotype, thus reducing the apparent heritability of a trait (14, 15).We sought to characterize explicitly how nonchromosomal modifiers collectively influence the heritability of a trait, colony size, in a system unique to yeast where we use a defined chromosomal genotype and vary the cytoplasmic genetic information. Yeast has at least four well-studied sources of inherited, nonchromosomal information: mitochondrial DNA, an endogenous dsRNA virus (16, 17), prions (18, 19), and a 2µ plasmid (20, 21).Our results show that the nonchromosomal contribution to heritability can be large, adding another dimension to the estimation of heritability in wild populations. Nonchromosomal information is not under the usual constraints of the nuclear genome. These nonchromosomal elements are extremely unstable: they mutate at higher frequencies than the DNA of the chromosomal genome, may be lost at high frequencies without loss of viability, and can vary in copy number from cell to cell. Thus, careful controls and measurements are necessary to characterize the effects of nonchromosomal modifiers.     

Cost-effectiveness of bone densitometry among Caucasian women and men without a prior fracture according to age and body weight

Summary

We used a microsimulation model to estimate the threshold body weights at which screening bone densitometry is cost-effective. Among women aged 55–65 years and men aged 55–75 years without a prior fracture, body weight can be used to identify those for whom bone densitometry is cost-effective.

Introduction

Bone densitometry may be more cost-effective for those with lower body weight since the prevalence of osteoporosis is higher for those with low body weight. Our purpose was to estimate weight thresholds below which bone densitometry is cost-effective for women and men without a prior clinical fracture at ages 55, 60, 65, 75, and 80 years.

Methods

We used a microsimulation model to estimate the costs and health benefits of bone densitometry and 5 years of fracture prevention therapy for those without prior fracture but with femoral neck osteoporosis (T-score?≤??2.5) and a 10-year hip fracture risk of ≥3%. Threshold pre-test probabilities of low BMD warranting drug therapy at which bone densitometry is cost-effective were calculated. Corresponding body weight thresholds were estimated using data from the Study of Osteoporotic Fractures (SOF), the Osteoporotic Fractures in Men (MrOS) study, and the National Health and Nutrition Examination Survey (NHANES) for 2005–2006.

Results

Assuming a willingness to pay of $75,000 per quality adjusted life year (QALY) and drug cost of $500/year, body weight thresholds below which bone densitometry is cost-effective for those without a prior fracture were 74, 90, and 100 kg, respectively, for women aged 55, 65, and 80 years; and were 67, 101, and 108 kg, respectively, for men aged 55, 75, and 80 years.

Conclusions

For women aged 55–65 years and men aged 55–75 years without a prior fracture, body weight can be used to select those for whom bone densitometry is cost-effective.     

10-Jahres-Ergebnisse nach Durom-Cup-Oberflächenersatz des proximalen Humerus bei Patienten mit rheumatoider Arthritis

Background

Little is known about the long-term results of shoulder arthroplasty in patients with rheumatoid arthritis (RA). The goal of the present study was the clinical and radiological evaluation of a cemented resurfacing of the humeral head in patients with RA after a minimum follow-up of 10 years.

Patients and methods

From 1997–2000 a total of 42 cemented humeral head resurfacing hemi-arthroplasties were performed in 35 patients with RA (average age 61 years) and included in a prospective long-term observational study with follow-up evaluations at 3, 12, >?60 and >?120 months postoperatively. At an average of 131?±?21 months 16 shoulders (14 patients, average age 70.9 years) could be evaluated by the Constant Murley score (CMS) and standard radiographs. For seven patients who were unable to attend hospital a CMS self-evaluation form was used and X-rays were made elsewhere and sent for analysis.

Results

The average total CMS was 62.6?±?10.6 points (pre-operative 20.8?±?8.3 points) and 88?% of the patients were satisfied or very satisfied with the results. Radiographically, a progressive proximal migration of the center of rotation and a continuous increase of the glenoid depth were observed between 3 and 130 months post-operatively. However, the radiographic progression did not correlate with either CMS values or with patient satisfaction.

Conclusions

The cemented humeral head resurfacing as a hemi-arthroplasty represents a valuable option for the treatment of advanced shoulder RA in elderly patients.     

Differential roles of inferior frontal and inferior parietal cortex in task switching: Evidence from stimulus‐categorization switching and response‐modality switching

We used fMRI to investigate both common and differential neural mechanisms underlying two distinct types of switching requirements, namely switching between stimulus categorizations (color vs. form) and switching between response modalities (hand vs. foot responses). Both types of switching induced similar behavioral shift costs. However, at the neural level, switching between stimulus categorizations led to left‐hemispheric activations including the inferior frontal gyrus as well as the intraparietal sulcus extending to the superior parietal gyrus and the supramarginal gyrus. In contrast, switching between response modalities was associated mainly with left‐hemispheric activation of the intraparietal sulcus and the supramarginal gyrus. A conjunction analysis indicated common activation of the left intraparietal sulcus and the supramarginal gyrus for both types of switching. Together, these results qualify previous claims about a general role of the left prefrontal cortex in task control by suggesting that the left inferior frontal gyrus is specifically involved in switching between stimulus categorizations, whereas parietal cortex is more generally implicated in the selection of action rules. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.