Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia

Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2–20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology

Can Paris pledges avert severe climate change?

Current international climate negotiations seek to catalyze global emissions reductions through a system of nationally determined country-level emissions reduction targets that would be regularly updated. These "Intended Nationally Determined Contributions" (INDC) would constitute the core of mitigation commitments under any agreement struck at the upcoming Paris Conference of the Parties to the United Nations Framework Convention on Climate Change (UNFCCC). With INDCs now reported from more than 150 countries and covering around 90% of global emissions, we can begin to assess the role of this round of INDCs in facilitating or frustrating achievement of longer-term climate goals. In this context, it is important to understand what these INDCs collectively deliver in terms of two objectives. First, how much do they reduce the probability of the highest levels of global mean surface temperature change? Second, how much do they improve the odds of achieving the international goal of limiting temperature change to under 2-degrees C relative to preindustrial levels? Although much discussion has focused on the latter objective, the former is equally important when viewing climate mitigation from a risk-management perspective