Genome-wide association studies of a broad spectrum of antisocial behavior

IMPORTANCE: Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified.OBJECTIVES: To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium.DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals).MAIN OUTCOME AND MEASURES: This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges.RESULTS: The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R-2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P =.005) was detected.CONCLUSIONS AND RELEVANCE: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.</p

Pelvic floor dysfunction 6 years post-anal sphincter tear at the time of vaginal delivery.

INTRODUCTION AND HYPOTHESIS: This study aims to estimate fecal, urinary incontinence, and sexual function 6 years after an obstetrical anal sphincter tear. METHODS: Among 13,213 women who had a vaginal delivery of a cephalic singleton at term, 196 women sustained an anal sphincter tear. They were matched to 588 controls. Validated questionnaires grading fecal and urinary incontinence, and sexual dysfunction were completed by the participants. RESULTS: Severe fecal incontinence was more frequently reported by women who had sustained an anal sphincter tear compared to the controls. Women with an anal sphincter tear had no increased risk of urinary incontinence, but reported significantly more pain, difficulty with vaginal lubrication, and difficulty achieving orgasm compared to the controls. A fetal occiput posterior position during childbirth was an independent risk factor for both severe urinary incontinence and severe sexual dysfunction. CONCLUSIONS: Fecal incontinence is strongly associated with an anal sphincter tear. A fetal occiput posterior position represents a risk factor for urinary incontinence and sexual dysfunction

A repression-derepression mechanism regulating the transcription of human immunodeficiency virus type 1 in primary T cells.

BACKGROUND: Despite some controversy regarding the preferential infection and replication of human immunodeficiency virus type 1 (HIV-1), it appears that primary T lymphocytes, in their quiescent state, are nonpermissive for viral expression and propagation. Massive activation of viral gene expression occurs only when the host lymphocyte is activated. These observations prompted us to investigate the transcriptional regulation of HIV-1 in resting or activated T cells that were isolated from cord blood or adult peripheral blood. MATERIALS AND METHODS: To this end, we employed cellular purification and phenotyping techniques, in vitro protein-DNA binding studies, functional transactivation assays using proteins isolated from cord blood or adult peripheral blood T lymphocytes, and transfection experiments in primary T cells. RESULTS: We showed that transcription from the HIV-1 long terminal repeat is repressed in resting naive T lymphocytes; whereas, mitogenically stimulated CD4+ cells form an activator that derepresses transcription. Negative and positive regulation act through a repressor-activator target sequence (RATS), which shares homology with the interleukin-2 (IL-2) purine-rich response element, through the adjacent binding site of the nuclear factor of activated T cells (NFAT), and weakly, through the KB region. CONCLUSIONS: This regulation exerted by cellular transcription factors can account for several important features of HIV-1 expression in primary CD4+ cells. Tight repression in resting naive T helper cells may be a main cause of viral latency and transcriptional activation accounts for massive viral production in activated T lymphocytes