A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose.

We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (p<1.5 x 10(-7)) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that approximately 30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target VKORC1 and another approximately 12% by two non-synonymous SNPs (*2, *3) in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p<10(-78)) at SNPs clustering near VKORC1 and the second lowest p-values (p<10(-31)) emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (p = 8.3 x 10(-10)) that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.

Communication patterns for interconnecting and composing medical systems.

This paper proposes a set of communication patterns to enable the construction of medical systems by composing devices and apps in Integrated Clinical Environments (ICE). These patterns abstract away the details of communication tasks, reduce engineering overhead, and ease compositional reasoning of the system. The proposed patterns have been successfully implemented on top of two distinct platforms (i.e., RTI Connext and Vert.x) to allow for experimentation.

Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder.

Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic 'hub' genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders.

Flowering of strict photoperiodic Nicotiana varieties in non-inductive conditions by transgenic approaches.

The genus Nicotiana contains species and varieties that respond differently to photoperiod for flowering time control as day-neutral, short-day and long-day plants. In classical photoperiodism studies, these varieties have been widely used to analyse the physiological nature for floral induction by day length. Since key regulators for flowering time control by day length have been identified in Arabidopsis thaliana by molecular genetic studies, it was intriguing to analyse how closely related plants in the Nicotiana genus with opposite photoperiodic requirements respond to certain flowering time regulators. SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) and FRUITFULL (FUL) are two MADS box genes that are involved in the regulation of flowering time in Arabidopsis. SOC1 is a central flowering time pathway integrator, whereas the exact role of FUL for floral induction has not been established yet. The putative Nicotiana orthologs of SOC1 and FUL, NtSOC1 and NtFUL, were studied in day-neutral tobacco Nicotiana tabacum cv Hicks, in short-day tobacco N. tabacum cv Hicks Maryland Mammoth (MM) and long-day N. sylvestris plants. Both genes were similarly expressed under short- and long-day conditions in day-neutral and short-day tobaccos, but showed a different expression pattern in N. sylvestris. Overexpression of NtSOC1 and NtFUL caused flowering either in strict short-day (NtSOC1) or long-day (NtFUL) Nicotiana varieties under non-inductive photoperiods, indicating that these genes might be limiting for floral induction under non-inductive conditions in different Nicotiana varieties.