Assessing the Probability that a Finding Is Genuine for Large-Scale Genetic Association Studies

Genetic association studies routinely involve massive numbers of statistical tests accompanied by P-values. Whole genome sequencing technologies increased the potential number of tested variants to tens of millions. The more tests are performed, the smaller P-value is required to be deemed significant. However, a small P-value is not equivalent to small chances of a spurious finding and significance thresholds may fail to serve as efficient filters against false results. While the Bayesian approach can provide a direct assessment of the probability that a finding is spurious, its adoption in association studies has been slow, due in part to the ubiquity of P-values and the automated way they are, as a rule, produced by software packages. Attempts to design simple ways to convert an association P-value into the probability that a finding is spurious have been met with difficulties. The False Positive Report Probability (FPRP) method has gained increasing popularity. However, FPRP is not designed to estimate the probability for a particular finding, because it is defined for an entire region of hypothetical findings with P-values at least as small as the one observed for that finding. Here we propose a method that lets researchers extract probability that a finding is spurious directly from a P-value. Considering the counterpart of that probability, we term this method POFIG: the Probability that a Finding is Genuine. Our approach shares FPRP''s simplicity, but gives a valid probability that a finding is spurious given a P-value. In addition to straightforward interpretation, POFIG has desirable statistical properties. The POFIG average across a set of tentative associations provides an estimated proportion of false discoveries in that set. POFIGs are easily combined across studies and are immune to multiple testing and selection bias. We illustrate an application of POFIG method via analysis of GWAS associations with Crohn''s disease.     

The single-cell epigenomic and transcriptional landscape of immunity to influenza vaccination

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Models for the mechanism for activating copper-zinc superoxide dismutase in the absence of the CCS Cu chaperone in Arabidopsis

Copper-zinc superoxide dismutase (CuZnSOD; CSD) is an important antioxidant enzyme for oxidative stress protection. To date, two activation pathways have been identified in many species. One requiring the CCS, Cu chaperone for SOD, to insert Cu and activate CSD (referred to as CCS-dependent pathway), and the other works independently of CCS (referred to as CCS-independent pathway). In our previous study, we suggest an unidentified factor will work with glutathione (GSH) for CSD activation in the absence of the CCS. Here, two models of the CCS-independent mechanism are proposed. The role of the unidentified factor may work as a scaffold protein, which provides a platform for the CSD protein and Cu-GSH to interact, or as a Cu carrier, which itself can bind Cu and interact with CSD proteins. We also suggest that the CSD protein conformation at C-terminal is important in providing a docking site for unidentified factor to access.     

Isolation and analysis of the human MEKA gene encoding a retina-specific protein

We have isolated and sequenced a human gene encoding photoreceptor cell-specific MEKA protein. The protein coding region was separated into three exons, which encoded 246 amino acid residues with a molecular weight of 28,311. The coding region of the human gene exhibited the homologies of 90.7% nucleotides and 88.5% amino acids with those of the bovine cDNA. Southern blot analysis revealed that the human MEKA gene has a single copy number. However, the anti-bovine MEKA stained both rod and cone photoreceptor cells in the human retina.     

Purification and characterization of two distinct Ca2+-activated proteinases from hearts of hypertensive rats

Two distinct Ca2+-activated proteinases were purified and characterized from hearts of hypertensive rats. Ca2+-activated proteinases I and II, having low and high Ca2+ requirements, respectively, were first separated by DEAE-cellulose chromatography. The enzymes were then purified individually by different column procedures: chromatography on phenyl-Sepharose, then Sephadex G-200 for proteinase I and reactive-red agarose for proteinase II. The apparent molecular weight of purified proteinase I was 125 000 and that for purified proteinase II was 110 000. Both enzymes are heterodimers made up of a larger catalytic subunit and a smaller subunit devoid of proteinase activity. Ca2+ concentrations for half-maximal activation were 5 microM for proteinase I and 200 microM for proteinase II. Both enzymes were inhibited by sulfhydryl-modifying agents, but exhibited different characteristics in the auto-digestion reaction in the presence of Ca2+. Proteinases I and II were also purified from hearts of normotensive rats and shown to be identical to their respective counterparts from hearts of hypertensive rats. However, proteinase II activity in hypertensive rat hearts was significantly elevated as compared to controls.     

Effects of monoclonal antibodies to bovine and Paracoccus denitrificans cytochromes c on reactions with oxidase, reductase and peroxidase

The effects of monoclonal antibodies to bovine and Paracoccus denitrificans cytochromes c (Kuo, L.M. and Davies, H.C. (1983) Mol. Immunol. 20, 827-838) in the reactions of the cytochromes c with cytochrome c oxidase, reductase and peroxidase were studied. Spectrophotometric assays were employed, under conditions where binding of cytochrome c to the enzymes appears to be rate-limiting. Less than stoichiometric amounts of antibodies to P. denitrificans cytochrome c added to the cytochrome rendered some of it nonoxidizable or nonreducible by the P. denitrificans membrane-bound electron transport system and decreased the rate constant with the remaining cytochrome c. The antibodies appear to affect both electron transport reactions (blocking effects) with the oxidase and reductase and binding effects (effects on rate constants) and to distinguish between the two. Different ratios of antibody site to cytochrome c gave different extents of blocking of the reductase as compared with the oxidase reaction. Differences were also apparent in the effect of these antibodies on the reaction of yeast peroxidase and the oxidase with the P. denitrificans cytochrome c. Antibodies to bovine and P. denitrificans cytochromes c had considerably less effect on the reactions of the bovine cytochrome with bovine oxidase and reductase. One antibody was inhibitory to the oxidase reaction with bovine cytochrome c, but not to that with the reductase. Also, an antibody which inhibited the oxidase reaction had no effect on the reaction with yeast peroxidase. The data give evidence that the interaction areas on cytochrome c for oxidase and reductase and peroxidase are not identical, although they may be nearby.     

Identification of a retina-specific MEKA protein as a 33 K protein

A photoreceptor-specific MEKA protein was purified from bovine retinal soluble fraction. The purified sample was eluted as a single peak of 74 kDa protein from a Superose column, which was dissolved into three components, MEKA protein (32 kDa), beta-(36 kDa) and gamma-(10 kDa) subunits of transducin on a SDS-PAGE. From several lines of evidence, we concluded that MEKA protein is identical with a 33k phosphoprotein reported by Lee et al (1).