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New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D--in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1--and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 – 50, P < 2.14 × 10−6), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD)1, epilepsy and severe neurodevelopmental disorders (DD/ID)2, though in some shared genes different mutation types are implicated. Most genes described here however are not implicated in neurodevelopment and we demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more risk genes await discovery using this approach.

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E–10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E–8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.

A poem is presented.

While exploring an unknown environment, an intelligent agent has only its sensors to guide its actions. Each sensor’s ability to provide accurate information depends on the environment’s characteristics. If the agent does not know these characteristics, how can it determine which sensors to rely on? This problem is exacerbated by sensing anomalies: cases where sensor(s) are working but the readings lead to an incorrect interpretation of the environment, e.g. laser sensors cannot detect glass. This work addresses the following research question: Can an inconsistency-based sensing accuracy indicator, which relies solely on fused sensor readings, be used to detect and characterize sensing anomalies in unknown environments? A novel inconsistency-based approach was investigated for sensing anomaly detection and characterization by a mobile robot using range sensing for mapping. Based on the hypothesis that sensing anomalies manifest as inconsistent sensor readings, the approach employed Dempster-Shafer theory and six metrics from the evidential literature to measure the magnitude of inconsistency. These were applied directly to fused sensor data with a threshold, forming an indicator, used to distinguish minor noise from anomalous readings. Experiments with real sensor data from four indoor and two outdoor environments showed that three of the six evidential inconsistency metrics can partially address the issue of noticing sensing anomalies in unknown environments. Polaroid sonar sensors, SICK laser range finders, and a Canesta range camera were used. Despite extensive training in known environments, the indicators could not reliably detect sensing anomalies, i.e. distinguish them from ordinary noise. However, sensing accuracy could be estimated (correlations with sensor error exceeded 0.8) and regions with suspect readings could be isolated. Trained indicators failed to rank sensors, but improved map quality by resetting suspect regions (up to 57.65%) or guiding sensor selection (up to 75.86%). This work contributes to the robotics and uncertainty in artificial intelligence communities by establishing the use of evidential metrics for adapting a single sensor or identifying the most accurate sensor to optimize the sensing accuracy in unknown environments. Future applications could enable intelligent systems to switch information sources to optimize mission performance and identify the reliability of sources for different environments.

Four couples who had the weddings they'd always wanted-- without spending the moon-- share it all: tender courtships and proposals, plans, budgets, and each bride's personal touches that made her Big Day special.

The Eckhardts of Houston, Texas, had 21 credit cards-- and debts totaling $46,000. Here's how a credit counselor is helping them get their heads above water.

The means by which a credit counselor helped Lisa and Wells Eckhardt regain control of their budget is described. At one point, the couple had 21 credit cards and debts totaling $46,000.