Polygenic Risk Score Contribution to Psychosis Prediction in a Target Population of Persons at Clinical High Risk.

OBJECTIVE: The 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%-25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator. METHODS: Persons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis. RESULTS: For Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2liability (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory. CONCLUSIONS: The PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.

Evidence that endogenous formaldehyde produces immunogenic and atherogenic adduct epitopes.

Endogenous formaldehyde is abundantly present in our bodies, at around 100 µM under normal conditions. While such high steady state levels of formaldehyde may be derived by enzymatic reactions including oxidative demethylation/deamination and myeloperoxidation, it is unclear whether endogenous formaldehyde can initiate and/or promote diseases in humans. Here, we show that fluorescent malondialdehyde-formaldehyde (M2FA)-lysine adducts are immunogenic without adjuvants in mice. Natural antibody titers against M2FA are elevated in atherosclerosis-prone mice. Staining with an antibody against M2FA demonstrated that M2FA is present in plaque found on the aortic valve of ApoE -/- mice. To mimic inflammation during atherogenesis, human myeloperoxidase was incubated with glycine, H2O2, malondialdehyde, and a lysine analog in PBS at a physiological temperature, which resulted in M2FA generation. These results strongly suggest that the 1,4-dihydropyridine-type of lysine adducts observed in atherosclerosis lesions are likely produced by endogenous formaldehyde and malondialdehyde with lysine. These highly fluorescent M2FA adducts may play important roles in human inflammatory and degenerative diseases.

Revealing substituent effects on the electronic structure and planarity of Ni-porphyrins.

Using density functional theory, we have studied the effects on structural and electronic consequences (including HOMO-LUMO energy gaps, vertical ionization potentials (IPv), and vertical electron affinities (EAv)) of the following two factors: (a) meso- and ß-substituents acting as inductive donors (CH3), inductive acceptors that are electron-donating through resonance (Br), inductive electron acceptors (CF3), and resonance enabled acceptors (NO2); and (b) complete replacement of pyrrole nitrogens with P-atoms. The principal results of the study are: (1) For the bare Ni-porphyrin, the solvents were found not to affect the HOMO-LUMO gaps but to change the IPv and EAv noticeably. (2) In the series CH3 → Br → CF3 → NO2 the HOMO-LUMO energy gaps, IPv, and EAv increase for both meso- and ß-substituents. The ruffling distortion of the porphyrin core is retained, and becomes stronger for the two acceptor groups. In general, effects of meso-substituents on the ruffling distortion of the porphyrin core is more pronounced. (3) Most significantly, complete replacement of pyrrole nitrogens in the NiP with phosphorus atoms produces the species, NiP(P)4, with the structural and electronic features drastically different from the original NiP. This implies that NiP(P)4 can possess interesting and unusual novel properties, including aromaticity and reactivity, leading to its various beneficial potential applications. Furthermore, NiP(P)4 high stability both in the gas phase and different solvents was shown, implying the feasibility of its synthesis.