Variation in _PNPLA3_ is associated with outcomes in alcoholic liver disease

Two recent genome-wide association studies have described associations of SNP variants in _PNPLA3_ with nonalcoholic fatty liver and plasma liver enzyme levels in population based cohorts. We investigated the contributions of these variants to clinical outcomes in Mestizo subjects with a history of excessive alcohol consumption. We show that non-synonymous variant rs738409[G] (I148M) in _PNPLA3_ is strongly associated with alcoholic liver disease and progression to alcoholic cirrhosis (unadjusted OR = 2.25, P = 1.7x10^-10^; ancestry-adjusted OR = 1.79, P = 1.9x10^-5^)

Clinical validity assessment of a breast cancer risk model combining genetic and clinical information

_Background:_ The extent to which common genetic variation can assist in breast cancer (BCa) risk assessment is unclear. We assessed the addition of risk information from a panel of BCa-associated single nucleotide polymorphisms (SNPs) on risk stratification offered by the Gail Model.

_Methods:_ We selected 7 validated SNPs from the literature and genotyped them among white women in a nested case-control study within the Women’s Health Initiative Clinical Trial. To model SNP risk, previously published odds ratios were combined multiplicatively. To produce a combined clinical/genetic risk, Gail Model risk estimates were multiplied by combined SNP odds ratios. We assessed classification performance using reclassification tables and receiver operating characteristic (ROC) curves. 

_Results:_ The SNP risk score was well calibrated and nearly independent of Gail risk, and the combined predictor was more predictive than either Gail risk or SNP risk alone. In ROC curve analysis, the combined score had an area under the curve (AUC) of 0.594 compared to 0.557 for Gail risk alone. For reclassification with 5-year risk thresholds at 1.5% and 2%, the net reclassification index (NRI) was 0.085 (Z = 4.3, P = 1.0×10^-5^). Focusing on women with Gail 5-year risk of 1.5-2% results in an NRI of 0.195 (Z = 3.8, P = 8.6×10^−5^).

_Conclusions:_ Combining clinical risk factors and validated common genetic risk factors results in improvement in classification of BCa risks in white, postmenopausal women. This may have implications for informing primary prevention and/or screening strategies. Future research should assess the clinical utility of such strategies.
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Estimates of array and pool-construction variance for planning efficient DNA-pooling genome wide association studies

<p>Abstract</p> <p>Background</p> <p>Until recently, genome-wide association studies (GWAS) have been restricted to research groups with the budget necessary to genotype hundreds, if not thousands, of samples. Replacing individual genotyping with genotyping of DNA pools in Phase I of a GWAS has proven successful, and dramatically altered the financial feasibility of this approach. When conducting a pool-based GWAS, how well SNP allele frequency is estimated from a DNA pool will influence a study's power to detect associations. Here we address how to control the variance in allele frequency estimation when DNAs are pooled, and how to plan and conduct the most efficient well-powered pool-based GWAS.</p> <p>Methods</p> <p>By examining the variation in allele frequency estimation on SNP arrays between and within DNA pools we determine how array variance [var(e_array)] and pool-construction variance [var(e_construction)] contribute to the total variance of allele frequency estimation. This information is useful in deciding whether replicate arrays or replicate pools are most useful in reducing variance. Our analysis is based on 27 DNA pools ranging in size from 74 to 446 individual samples, genotyped on a collective total of 128 Illumina beadarrays: 24 1M-Single, 32 1M-Duo, and 72 660-Quad.</p> <p>Results</p> <p>For all three Illumina SNP array types our estimates of var(e_array) were similar, between 3-4 × 10^-4for normalized data. Var(e_construction) accounted for between 20-40% of pooling variance across 27 pools in normalized data.</p> <p>Conclusions</p> <p>We conclude that relative to var(e_array), var(e_construction) is of less importance in reducing the variance in allele frequency estimation from DNA pools; however, our data suggests that on average it may be more important than previously thought. We have prepared a simple online tool, PoolingPlanner (available at <url>http://www.kchew.ca/PoolingPlanner/</url>), which calculates the effective sample size (ESS) of a DNA pool given a range of replicate array values. ESS can be used in a power calculator to perform pool-adjusted calculations. This allows one to quickly calculate the loss of power associated with a pooling experiment to make an informed decision on whether a pool-based GWAS is worth pursuing.</p

Evidence for Positive Selection on a Number of MicroRNA Regulatory Interactions during Recent Human Evolution

MicroRNA (miRNA)–mediated gene regulation is of critical functional importance in animals and is thought to be largely constrained during evolution. However, little is known regarding evolutionary changes of the miRNA network and their role in human evolution. Here we show that a number of miRNA binding sites display high levels of population differentiation in humans and thus are likely targets of local adaptation. In a subset we demonstrate that allelic differences modulate miRNA regulation in mammalian cells, including an interaction between miR-155 and TYRP1, an important melanosomal enzyme associated with human pigmentary differences. We identify alternate alleles of TYRP1 that induce or disrupt miR-155 regulation and demonstrate that these alleles are selected with different modes among human populations, causing a strong negative correlation between the frequency of miR-155 regulation of TYRP1 in human populations and their latitude of residence. We propose that local adaptation of microRNA regulation acts as a rheostat to optimize TYRP1 expression in response to differential UV radiation. Our findings illustrate the evolutionary plasticity of the microRNA regulatory network in recent human evolution

The Role of Geography in Human Adaptation

Various observations argue for a role of adaptation in recent human evolution, including results from genome-wide studies and analyses of selection signals at candidate genes. Here, we use genome-wide SNP data from the HapMap and CEPH-Human Genome Diversity Panel samples to study the geographic distributions of putatively selected alleles at a range of geographic scales. We find that the average allele frequency divergence is highly predictive of the most extreme FST values across the whole genome. On a broad scale, the geographic distribution of putatively selected alleles almost invariably conforms to population clusters identified using randomly chosen genetic markers. Given this structure, there are surprisingly few fixed or nearly fixed differences between human populations. Among the nearly fixed differences that do exist, nearly all are due to fixation events that occurred outside of Africa, and most appear in East Asia. These patterns suggest that selection is often weak enough that neutral processes—especially population history, migration, and drift—exert powerful influences over the fate and geographic distribution of selected alleles

Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis

10.1371/journal.pone.0053830PLoS ONE81

Apnea of prematurity: from cause to treatment

Apnea of prematurity (AOP) is a common problem affecting premature infants, likely secondary to a “physiologic” immaturity of respiratory control that may be exacerbated by neonatal disease. These include altered ventilatory responses to hypoxia, hypercapnia, and altered sleep states, while the roles of gastroesophageal reflux and anemia remain controversial. Standard clinical management of the obstructive subtype of AOP includes prone positioning and continuous positive or nasal intermittent positive pressure ventilation to prevent pharyngeal collapse and alveolar atelectasis, while methylxanthine therapy is a mainstay of treatment of central apnea by stimulating the central nervous system and respiratory muscle function. Other therapies, including kangaroo care, red blood cell transfusions, and CO2 inhalation, require further study. The physiology and pathophysiology behind AOP are discussed, including the laryngeal chemoreflex and sensitivity to inhibitory neurotransmitters, as are the mechanisms by which different therapies may work and the potential long-term neurodevelopmental consequences of AOP and its treatment