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PURPOSE. Refractive errors, particularly myopia, are common and a leading cause of blind-ness. This study aimed to explore associations between medications and refractive error in an aging adult cohort and to determine whether childhood-onset refractive errors predict future medication use to provide novel insights into disease mechanisms.METHODS. The study compared the spherical equivalent values measured in 102,318 UK Biobank participants taking the 960 most commonly used medications. The strengths of associations were evaluated against the self-reported age of spectacle wear. The causality of refractive error changes was inferred using sensitivity and Mendelian randomization analyses.RESULTS. Anti-glaucoma drugs were associated with 1 to 2 diopters greater myopic refrac-tion, particularly in subjects who started wearing correction in the first two decades of life, potentially due to the association of higher intraocular pressure since early years with both myopia and, later in life, glaucoma. All classes of pain-control medications, including paracetamol, opiates, non-steroidal antiinflammatory drugs, and gabapentinoids, were associated with greater hyperopia (+0.68-1.15 diopters), after correction for deprivation, education, and polypharmacy and sensitivity analyses for common diagnoses. Oral hypoglycemics (metformin, gliburonide) were associated with myopia, as was allopurinol, and participants using bronchodilators (ipratropium and salbutamol) were more hyperopic.CONCLUSIONS. This study finds for the first time, to our knowledge, that medication use is associated with refractive error in adults. The novel finding that analgesics are associated with hyperopic refraction, and the possibility that multisite chronic pain predisposes to hyperopia, deserves further research. Some drugs, such as antihyperglycemic or bronchodilators, may directly alter refractive error. Intraocular pressure appears causative for myopia.

We tested the hypothesis that mating strategies with genomic information realise lower rates of inbreeding (∆F) than with pedigree information without compromising rates of genetic gain (∆G). We used stochastic simulation to compare ∆F and ∆G realised by two mating strategies with pedigree and genomic information in five breeding schemes. The two mating strategies were minimum-coancestry mating (MC) and minimising the covariance between ancestral genetic contributions (MCAC). We also simulated random mating (RAND) as a reference point. Generations were discrete. Animals were truncation-selected for a single trait that was controlled by 2000 quantitative trait loci, and the trait was observed for all selection candidates before selection. The criterion for selection was genomic-breeding values predicted by a ridge-regression model. Our results showed that MC and MCAC with genomic information realised 6% to 22% less ∆F than MC and MCAC with pedigree information without compromising ∆G across breeding schemes. MC and MCAC realised similar ∆F and ∆G. In turn, MC and MCAC with genomic information realised 28% to 44% less ∆F and up to 14% higher ∆G than RAND. These results indicated that MC and MCAC with genomic information are more effective than with pedigree information in controlling rates of inbreeding. This implies that genomic information should be applied to more than just prediction of breeding values in breeding schemes with truncation selection.

We reasoned that mating animals by minimising the covariance between ancestral contributions (MCAC mating) will generate less inbreeding and at least as much genetic gain as minimum-coancestry mating in breeding schemes where the animals are truncation-selected. We tested this hypothesis by stochastic simulation and compared the mating criteria in hierarchical and factorial breeding schemes, where the animals were selected based on breeding values predicted by animal-model BLUP. Random mating was included as a reference-mating criterion. We found that MCAC mating generated 4% to 8% less inbreeding than minimum-coancestry mating in the hierarchical and factorial breeding schemes without any loss in genetic gain. Moreover, it generated upto 28% less inbreeding and about 3% more genetic gain than random mating. The benefits of MCAC mating over minimum-coancestry mating are worthwhile because they can be achieved without extra costs or practical constraints. MCAC mating merely uses pedigree information to pair the animals more appropriately and is clearly a worthy alternative to minimum-coancestry mating and probably any other mating criterion. We believe, therefore, that MCAC mating should be used in breeding schemes where pedigree information is available. Udgivelsesdato: October We reasoned that mating animals by minimising the covariance between ancestral contributions (MCAC mating) will generate less inbreeding and at least as much genetic gain as minimum-coancestry mating in breeding schemes where the animals are truncation-selected. We tested this hypothesis by stochastic simulation and compared the mating criteria in hierarchical and factorial breeding schemes, where the animals were selected based on breeding values predicted by animal-model BLUP. Random mating was included as a reference-mating criterion. We found that MCAC mating generated 4% to 8% less inbreeding than minimum-coancestry mating in the hierarchical and factorial breeding schemes without any loss in genetic gain. Moreover, it generated upto 28% less inbreeding and about 3% more genetic gain than random mating. The benefits of MCAC mating over minimum-coancestry mating are worthwhile because they can be achieved without extra costs or practical constraints. MCAC mating merely uses pedigree information to pair the animals more appropriately and is clearly a worthy alternative to minimum-coancestry mating and probably any other mating criterion. We believe, therefore, that MCAC mating should be used in breeding schemes where pedigree information is available.

Within breeds and other captive populations, the risk of high inbreeding rates and loss of diversity can be high within (small) herds or subpopulations. When exchange of animals between different subpopulations is organised according to a rotational mating scheme, inbreeding rates can be restricted. Two such schemes, a breeding circle and a maximum avoidance of inbreeding scheme, are compared. In a breeding circle, flocks are organised in a circle where each flock serves as a donor flock for another flock, and the same donor–recipient combination is used in each breeding season. In the maximum inbreeding avoidance scheme, donor¿recipient combinations change each year so that the use of the same combination is postponed as long as possible. Data from the Kempisch Heideschaap were used with computer simulations to determine the long-term effects of different breeding schemes. Without exchanging rams between flocks, high inbreeding rates (>1.5% per year) occurred. Both rotational mating schemes reduced inbreeding rates to on average 0.16% per year and variation across flocks in inbreeding rates, caused by differences in flock size, almost disappeared. Inbreeding rates with maximum inbreeding avoidance were more variable than with a breeding circle. Moreover, a breeding circle is easier to implement and operate. Breeding circles are thus efficient and flexible and can also be efficient for other captive populations, such as zoo populations of endangered wild species

Context: Smaller brain volumes have consistently been found in patients with schizophrenia, particularly in gray matter and medial temporal lobe structures. Although several studies have investigated brain volumes in nonpsychotic relatives of patients with schizophrenia, results have been inconsistent. Objective: To determine the magnitude and extent of brain volume differences in first-degree relatives of schizophrenic patients. Data Sources: A systematic search was conducted to identify relevant studies. Computer searches of the MEDLINE database were performed for English-language articles published before July 2005. Relevant abstracts published in 2005 were also selected. Study Selection: Magnetic resonance imaging studies that examined differences in brain volumes between first-degree relatives of patients with schizophrenia and healthy control subjects were obtained through computerized databases, including MEDLINE. Studies had to report sufficient data for computation of effect sizes. Data Extraction: For each study, the Cohen d was calculated. Data extraction and calculation of the effect size were performed by 2 authors ( H. B. M. B. and A. A.) who reached a consensus in cases of uncertainty and discrepancies. All analyses were performed using the random-effects model. Data Synthesis: Twenty-five studies were identified as suitable for analysis and included 1065 independent first-degree relatives of patients, 679 patients with schizophrenia, and 1100 healthy control subjects. The largest difference between relatives and healthy control subjects was found in hippocampal volume, with relatives having smaller volumes than controls (d=0.31; 95% confidence interval [CI], 0.13-0.49; 9 effect sizes). Gray matter was smaller (d=0.18; 95% CI, 0.02-0.33; 7 effect sizes) and third-ventricle volume was larger (d=0.21; 95% CI, 0.03-0.40; 7 effect sizes) in relatives compared with healthy control subjects. Conclusion: Brain abnormalities are present in nonpsychotic first-degree relatives of patients with schizophrenia and are most pronounced in the hippocampus.

Within breeds and other captive populations, the risk of high inbreeding rates and loss of diversity can be high within (small) herds or subpopulations. When exchange of animals between different subpopulations is organised according to a rotational mating scheme, inbreeding rates can be restricted. Two such schemes, a breeding circle and a maximum avoidance of inbreeding scheme, are compared. In a breeding circle, flocks are organised in a circle where each flock serves as a donor flock for another flock, and the same donor–recipient combination is used in each breeding season. In the maximum inbreeding avoidance scheme, donor¿recipient combinations change each year so that the use of the same combination is postponed as long as possible. Data from the Kempisch Heideschaap were used with computer simulations to determine the long-term effects of different breeding schemes. Without exchanging rams between flocks, high inbreeding rates (>1.5% per year) occurred. Both rotational mating schemes reduced inbreeding rates to on average 0.16% per year and variation across flocks in inbreeding rates, caused by differences in flock size, almost disappeared. Inbreeding rates with maximum inbreeding avoidance were more variable than with a breeding circle. Moreover, a breeding circle is easier to implement and operate. Breeding circles are thus efficient and flexible and can also be efficient for other captive populations, such as zoo populations of endangered wild species

Context Smaller brain volumes have consistently been found in patients with schizophrenia, particularly in gray matter and medial temporal lobe structures. Although several studies have investigated brain volumes in nonpsychotic relatives of patients with schizophrenia, results have been inconsistent. Objective To determine the magnitude and extent of brain volume differences in first-degree relatives of schizophrenic patients. Data Sources A systematic search was conducted to identify relevant studies. Computer searches of the MEDLINE database were performed for English-language articles published before July 2005. Relevant abstracts published in 2005 were also selected. Study Selection Magnetic resonance imaging studies that examined differences in brain volumes between first-degree relatives of patients with schizophrenia and healthy control subjects were obtained through computerized databases, including MEDLINE. Studies had to report sufficient data for computation of effect sizes. Data Extraction For each study, the Cohen d was calculated. Data extraction and calculation of the effect size were performed by 2 authors (H.B.M.B. and A.A.) who reached a consensus in cases of uncertainty and discrepancies. All analyses were performed using the random-effects model. Data Synthesis Twenty-five studies were identified as suitable for analysis and included 1065 independent first-degree relatives of patients, 679 patients with schizophrenia, and 1100 healthy control subjects. The largest difference between relatives and healthy control subjects was found in hippocampal volume, with relatives having smaller volumes than controls (d = 0.31; 95% confidence interval [CI], 0.13-0.49; 9 effect sizes). Gray matter was smaller (d = 0.18; 95% CI, 0.02-0.33; 7 effect sizes) and third-ventricle volume was larger (d = 0.21; 95% CI, 0.03-0.40; 7 effect sizes) in relatives compared with healthy control subjects. Conclusion Brain abnormalities are present in nonpsychotic first-degree relatives of patients with schizophrenia and are most pronounced in the hippocampus.

International audience; There are selection methods available that allow the optimisation of genetic contributions of selection candidates for maximising the rate of genetic gain while restricting the rate of inbreeding. These methods imply selection on quadratic indices as the selection merit of a particular individual is a quadratic function of its estimated breeding value. This study provides deterministic predictions of genetic gain from selection on quadratic indices for a given set of resources (the number of candidates), heritability, and target rate of inbreeding. The rate of gain was obtained as a function of the accuracy of the Mendelian sampling term at the time of convergence of long-term contributions of selected candidates and the theoretical ideal rate of gain for a given rate of inbreeding after an exact allocation of long-term contributions to Mendelian sampling terms. The expected benefits from quadratic indices over traditional linear indices (i.e. truncation selection), both using BLUP breeding values, were quantified. The results clearly indicate higher gains from quadratic optimisation than from truncation selection. With constant rate of inbreeding and number of candidates, the benefits were generally largest for intermediate heritabilities but evident over the entire range. The advantage of quadratic indices was not highly sensitive to the rate of inbreeding for the constraints considered.

There are selection methods available that allow the optimisation of genetic contributions of selection candidates for maximising the rate of genetic gain while restricting the rate of inbreeding. These methods imply selection on quadratic indices as the selection merit of a particular individual is a quadratic function of its estimated breeding value. This study provides deterministic predictions of genetic gain from selection on quadratic indices for a given set of resources (the number of candidates), heritability, and target rate of inbreeding. The rate of gain was obtained as a function of the accuracy of the Mendelian sampling term at the time of convergence of long-term contributions of selected candidates and the theoretical ideal rate of gain for a given rate of inbreeding after an exact allocation of long-term contributions to Mendelian sampling terms. The expected benefits from quadratic indices over traditional linear indices (i.e. truncation selection), both using BLUP breeding values, were quantified. The results clearly indicate higher gains from quadratic optimisation than from truncation selection. With constant rate of inbreeding and number of candidates, the benefits were generally largest for intermediate heritabilities but evident over the entire range. The advantage of quadratic indices was not highly sensitive to the rate of inbreeding for the constraints considered.

Preterm birth is a complex disorder defined by gestations of less than 37 weeks. While preterm birth is estimated to have a significant genetic component, relative few genes have been associated with preterm birth. Polymorphism in one such gene, follicle-stimulating hormone receptor (FSHR), has been associated with preterm birth in Finnish and African American mothers but not other populations. To refine the genetic association of FSHR with preterm birth we conducted a fine-mapping study at the FSHR locus in a Finnish cohort. We sequenced a total of 44 kb, including protein-coding and conserved non-coding regions, in 127 preterm and 135 term mothers. Overall, we identified 288 single nucleotide variants and 65 insertion/deletions of 1–2 bp across all subjects. While no common SNPs in protein-coding regions were associated with preterm birth, including one previously associated with timing of fertilization, multiple SNPs spanning the first and second intron showed the strongest associations. Analysis of the associated SNPs revealed that they form both a protective (OR = 0.50, 95% CI = 0.25–0.93) as well as a risk (OR = 1.89, 95% CI = 1.08–3.39) haplotype with independent effects. In these haplotypes, two SNPs, rs12052281 and rs72822025, were predicted to disrupt ZEB1 and ELF3 transcription factor binding sites, respectively. Our results show that multiple haplotypes at FSHR are associated with preterm birth and we discuss the frequency and structure of these haplotypes outside of the Finnish population as a potential explanation for the absence of FSHR associations in some populations.