Meta-analysis of genome-wide association studies for extraversion:Findings from the Genetics of Personality Consortium

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion

Status Update and Interim Results from the Asymptomatic Carotid Surgery Trial-2 (ACST-2)

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved

HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer.

PURPOSE: Hepatobiliary adverse events (AEs) have been observed in a small proportion of patients with metastatic breast cancer (MBC) treated with lapatinib. This study sought to identify gene variants associated with lapatinib-induced ALT elevation and hepatobiliary AEs. PATIENTS AND METHODS: A two-stage pharmacogenetic investigation of ALT elevation was conducted in lapatinib-treated patients with MBC. Exploratory marker identification evaluated classical HLA alleles, candidate genes, and genome-wide screening in 37 cases with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls with ALT ≤ 1× ULN, selected from 901 lapatinib-treated patients in 12 trials. Markers achieving prespecified association thresholds were progressed to an independent confirmatory data set of 24 ALT cases and 155 controls selected from a subsequent trial of 374 lapatinib-treated patients. RESULTS: Of 58 variants associated with ALT elevation in the exploratory data set, four exceeded the prespecified significance threshold in the confirmatory analysis. These variants reside in the same MHC genomic locus and include HLA-DQA1*02:01. In the confirmatory study, DQA1*02:01 allele carriage was present in 71% of ALT cases and in 21% of controls (P < .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a predictor of liver safety risk in ALT cases versus noncases, DQA1*02:01 had negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 (95% CI 0.10 to 0.26), respectively. CONCLUSION: These results support a role for immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required to determine whether testing for DQA1*02:01 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment

The Contributions of Parental, Academic, School, and Peer Factors to Differences by Socioeconomic Status in Adolescents’ Locus of Control

An internal locus of control may be particularly valuable for youth with low socioeconomic status (SES), yet the mechanisms that externalize their control remain unclear. This study uses data on 16,450 US 8th graders surveyed for the National Education Longitudinal Study in 1988 and 1990. Results indicate family income is more closely associated with adolescents’ locus of control than parents’ occupations and educational attainment, and that race does not independently affect adolescents’ locus of control net of these other components of SES. Findings also indicate higher SES adolescents feel more internal locus of control in largest part because their parents discuss school more often with them, their homes have more books and other cognitive resources, they receive higher grades in middle school science and social studies, they are more likely to attend a private rather than public school, their friends are more academically oriented, and they feel more safe at school

Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort (Nature, (2020), 583, 7814, (90-95), 10.1038/s41586-020-2265-1)

An amendment to this paper has been published and can be accessed via a link at the top of the paper