Mendelian randomization (MR) is a valuable tool for detecting causal effects using genetic variant associations. Opportunities to apply MR are growing rapidly with the number of genome-wide association studies (GWAS). However, existing MR methods rely on strong assumptions that are often violated, leading to false positives. Correlated horizontal pleiotropy, which arises when variants affect both traits through a heritable shared factor, remains a particularly challenging problem. We propose a new MR method, Causal Analysis Using Summary Effect Estimates (CAUSE), that accounts for correlated and uncorrelated horizontal pleiotropic effects. We demonstrate in simulations that CAUSE avoids more false positives induced by correlated horizontal pleiotropy than other methods. Applied to traits studied in recent GWAS, we find that CAUSE detects causal relationships with strong literature support and avoids identifying most unlikely relationships. Our results suggest that shared heritable factors are common and may lead to many false positives using alternative methods.

Summary PTEN dysfunction plays a crucial role in the pathogenesis of hereditary and sporadic cancers. Here we show that PTEN homo-dimerizes, and in this active conformation exerts lipid phosphatase activity on PtdIns(3,4,5)P3. We demonstrate that catalytically inactive cancer-associated PTEN mutants hetero-dimerize with wild-type PTEN and constrain its phosphatase activity in a dominant-negative manner. To study the consequences of homo- and hetero-dimerization of wild-type and mutant PTEN in vivo, we generated Pten knock-in mice harboring two cancer-associated PTEN mutations (PtenC124S and PtenG129E). Heterozygous PtenC124S/+ and PtenG129E/+ cells and tissues exhibit increased sensitivity to PI3-K/Akt activation compared to wild-type and Pten+/- counterparts, while this difference is no longer apparent between PtenC124S/- and Pten-/- cells. Notably, PtenKI mice are more tumor-prone and display features reminiscent of complete Pten loss. Our findings reveal that PTEN loss and PTEN mutations are not synonymous, and define a new working model for the function and regulation of PTEN.

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

Stressful life experiences are known to be a precipitating factor for many mental disorders. The social defeat model induces behavioral responses in rodents (e.g. reduced social interaction) that are similar to behavioral patterns associated with mood disorders. The model has contributed to the discovery of novel mechanisms regulating behavioral responses to stress, but its utility has been largely limited to males. This is disadvantageous because most mood disorders have a higher incidence in women versus men. Male and female California mice (Peromyscus californicus) aggressively defend territories, which allowed us to observe the effects of social defeat in both sexes. In two experiments, mice were exposed to three social defeat or control episodes. Mice were then behaviorally phenotyped, and indirect markers of brain activity and corticosterone responses to a novel social stimulus were assessed. Sex differences in behavioral responses to social stress were long lasting (4 wks). Social defeat reduced social interaction responses in females but not males. In females, social defeat induced an increase in the number of phosphorylated CREB positive cells in the nucleus accumbens shell after exposure to a novel social stimulus. This effect of defeat was not observed in males. The effects of defeat in females were limited to social contexts, as there were no differences in exploratory behavior in the open field or light-dark box test. These data suggest that California mice could be a useful model for studying sex differences in behavioral responses to stress, particularly in neurobiological mechanisms that are involved with the regulation of social behavior.