Poor inhibitory control is a known risk factor for substance use disorders, making it a priority to identify the determinants of these deficits. The aim of the current study was to identify genetic associations with inhibitory control using the stop signal task in a large sample (n = 934) of healthy young adults of European ancestry. We genotyped the subjects genome-wide and then used a hierarchical approach in which we tested seven a priori single nucleotide polymorphisms (SNPs) previously associated with stop signal task performance, approximately 9,000 SNPs designated as high-value addiction (HVA) markers by the SmokeScreen array, and approximately five million genotyped and imputed SNPs, followed by a gene-based association analysis using the resultant p values. A priori SNP analyses revealed nominally significant associations between response inhibition and one locus in HTR2A (rs6313; p = .04, dominance model, uncorrected) in the same direction as prior findings. A nominally significant association was also found in one locus in ANKK1 (rs1800497; p = .03, uncorrected), although in the opposite direction of previous reports. After accounting for multiple comparisons, the HVA, genome-wide, and gene-based analyses yielded no significant findings. This study implicates variation in serotonergic and dopaminergic genes while underscoring the difficulty of detecting the influence of individual SNPs, even when biological information is used to prioritize testing. Although such small effect sizes suggest limited utility of individual SNPs in predicting risk for addiction or other impulse control disorders, they may nonetheless shed light on complex biological processes underlying poor inhibitory control. (PsycINFO Database Record

Impulsive personality traits are heritable risk factors and putative endophenotypes for addiction and other psychiatric disorders involving disinhibition. This study examined the genetic basis of impulsive personality traits, defined as scores on the Barratt Impulsiveness Scale (BIS-11) and the UPPS-P Impulsive Behavior Scale (UPPS-P). In 983 healthy young adults of European ancestry, the study examined genetic variation in relation to a combined phenotype of seven subscales based on high phenotypic intercorrelations. The study first tested 14 a priori loci that have previously been associated impulsive personality traits or closely related constructs. Second, the study included an exploratory genome-wide scan (i.e., GWAS), acknowledging that only relatively large effects would be detectable in a sample size of ~ 1000. A priori SNP analyses revealed a significant association between the combined impulsivity phenotype and two SNPs within the 5-HT2a receptor gene (HTR2A; rs6313 and rs6311). Follow-up analyses suggested that the effects were specific to the Motor and Non-planning subscales on the BIS-11, and also that the two loci were in linkage disequilibrium. The GWAS yielded no statistically significant findings. This study further implicates loci within HTR2A with certain forms of self-reported impulsivity and identifies candidates for future investigation from the genome-wide analyses.

The process of plant speciation often involves the evolution of divergent ecotypes in response to differences in soil water availability between habitats. While the same set of traits is frequently associated with xeric/mesic ecotype divergence, it is unknown whether those traits evolve independently or if they evolve in tandem as a result of genetic colocalization either by pleiotropy or genetic linkage. The self-fertilizing C4 grass species Panicum hallii includes two major ecotypes found in xeric (var. hallii) or mesic (var. filipes) habitats. We constructed the first linkage map for P. hallii by genotyping a reduced representation genomic library of an F2 population derived from an intercross of var. hallii and filipes. We then evaluated the genetic architecture of divergence between these ecotypes through quantitative trait locus (QTL) mapping. Overall, we mapped QTLs for nine morphological traits that are involved in the divergence between the ecotypes. QTLs for five key ecotype-differentiating traits all colocalized to the same region of linkage group five. Leaf physiological traits were less divergent between ecotypes, but we still mapped five physiological QTLs. We also discovered a two-locus Dobzhansky-Muller hybrid incompatibility. Our study suggests that ecotype-differentiating traits may evolve in tandem as a result of genetic colocalization.

The process of plant speciation often involves the evolution of divergent ecotypes in response to differences in soil water availability between habitats. While the same set of traits is frequently associated with xeric/mesic ecotype divergence, it is unknown whether those traits evolve independently or if they evolve in tandem as a result of genetic colocalization either by pleiotropy or genetic linkage. The self-fertilizing C4 grass species Panicum hallii includes two major ecotypes found in xeric (var. hallii) or mesic (var. filipes) habitats. We constructed the first linkage map for P. hallii by genotyping a reduced representation genomic library of an F2 population derived from an intercross of var. hallii and filipes. We then evaluated the genetic architecture of divergence between these ecotypes through quantitative trait locus (QTL) mapping. Overall, we mapped QTLs for nine morphological traits that are involved in the divergence between the ecotypes. QTLs for five key ecotype-differentiating traits all colocalized to the same region of linkage group five. Leaf physiological traits were less divergent between ecotypes, but we still mapped five physiological QTLs. We also discovered a two-locus Dobzhansky-Muller hybrid incompatibility. Our study suggests that ecotype-differentiating traits may evolve in tandem as a result of genetic colocalization.

High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer^1,2, but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. Here we develop a label-free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.