The role of neuroticism in self-harm and suicidal ideation: results from two UK population-based cohorts.

BACKGROUND: Self-harm is common, debilitating and associated with completed suicide and increased all-cause mortality, but there is uncertainty about its causal risk factors, limiting risk assessment and effective management. Neuroticism is a stable personality trait associated with self-harm and suicidal ideation, and correlated with coping styles, but its value as an independent predictor of these outcomes is disputed. METHODS: Prior history of hospital-treated self-harm was obtained by record-linkage to administrative health data in Generation Scotland:Scottish Family Health Study (N = 15,798; self-harm cases = 339) and by a self-report variable in UK Biobank (N = 35,227; self-harm cases = 772). Neuroticism in both cohorts was measured using the Eysenck Personality Questionnaire-Short Form. Associations of neuroticism with self-harm were tested using multivariable regression following adjustment for age, sex, cognitive ability, educational attainment, socioeconomic deprivation, and relationship status. A subset of GS:SFHS was followed-up with suicidal ideation elicited by self-report (n = 3342, suicidal ideation cases = 158) and coping styles measured by the Coping Inventory for Stressful Situations. The relationship of neuroticism to suicidal ideation, and the role of coping style, was then investigated using multivariable logistic regression. RESULTS: Neuroticism was positively associated with hospital-associated self-harm in GS:SFHS (per EPQ-SF unit odds ratio 1.2 95% credible interval 1.1-1.2, pFDR 0.0003) and UKB (per EPQ-SF unit odds ratio 1.1 95% confidence interval 1.1-1.2, pFDR 9.8 × 10-17). Neuroticism, and the neuroticism-correlated coping style, emotion-oriented coping (EoC), were also associated with suicidal ideation in multivariable models. CONCLUSIONS: Neuroticism is an independent predictor of hospital-treated self-harm risk. Neuroticism and emotion-orientated coping styles are also predictive of suicidal ideation.

Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766).

Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV.

The one and the many: effects of the cell adhesion molecule pathway on neuropsychological function in psychosis.

BACKGROUND: Genetic studies of single gene variants have been criticized as providing a simplistic characterization of the genetic basis of illness risk that ignores the effects of other variants within the same biological pathways. Of candidate biological pathways for schizophrenia (SZ), the cell adhesion molecule (CAM) pathway has repeatedly been linked to both psychosis and neurocognitive dysfunction. Here we tested, using risk allele scores derived from the Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), whether alleles within the CAM pathway were correlated with poorer neuropsychological function in patients. METHOD: In total, 424 patients with psychosis were assessed in areas of cognitive ability typically found to be impaired in SZ: intelligence quotient, memory, working memory and attentional control. CAM pathway genes were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Alleles within these genes identified as significantly associated with SZ risk in the PGC-SCZ were then used to calculate a CAM pathway-based polygenic risk allele score for each patient and these scores were tested for association with cognitive ability. RESULTS: Increased CAM pathway polygenic risk scores were significantly associated with poorer performance on measures of memory and attention, explaining 1-3% of variation on these measures. Notably, the most strongly associated single nucleotide polymorphism (SNP) in the CAM pathway (rs9272105 within HLA-DQA1) explained a similar amount of variance in attentional control, but not memory, as the polygenic risk analysis. CONCLUSIONS: These data support a role for the CAM pathway in cognitive function, both at the level of individual SNPs and the wider pathway. In so doing these data highlight the value of pathway-based polygenic risk score studies as well as single gene studies for understanding SZ-associated deficits in cognition.

Genetic variants in AVPR1A linked to autism predict amygdala activation and personality traits in healthy humans.

In mammals, the neuropeptide vasopressin is a key molecule for complex emotional and social behaviours. Two microsatellite polymorphisms, RS1 and RS3, near the promoter of AVPR1A, encoding the receptor subtype most heavily implicated in behaviour regulation, have been linked to autism and behavioural traits. However, the impact of these variants on human brain function is unknown. Here we show that human amygdala function is strongly associated with genetic variation in AVPR1A. Using an imaging genetics approach in a sample of 121 volunteers studied with an emotional face-matching paradigm, we found that differential activation of amygdala is observed in carriers of risk alleles for RS3 and RS1. Alleles in RS1 previously reported to be significantly over- and undertransmitted to autistic probands showed opposing effects on amygdala activation. Furthermore, we show functional difference in human brain between short and long repeat lengths that mirror findings recently obtained in a corresponding variant in voles. Our results indicate a neural mechanism mediating genetic risk for autism through an impact on amygdala signalling and provide a rationale for exploring therapeutic strategies aimed at abnormal amygdala function in this disorder.

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk.

The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia.

Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women.

OBJECTIVE: To examine whether postmenopausal women with diabetes experienced a higher incidence of hip fracture than women without diabetes. RESEARCH DESIGN AND METHODS: A prospective cohort of 32,089 postmenopausal women residing in Iowa were surveyed by mail in 1986 and followed for 11 years. Diabetes status and other potential risk factors were assessed by questionnaires at baseline; incidence of hip fracture was ascertained by follow-up questionnaires. RESULTS: A total of 490 hip fractures were reported over 306,900 person-years of follow-up. After adjustment for age, smoking status, estrogen use, BMI, and waist-to-hip ratio, women with type 1 diabetes (n = 47) were 12.25 times (95% CI 5.05-29.73) more likely to report an incident hip fracture than women without diabetes. Women with type 2 diabetes had a 1.70-fold higher risk (1.21-2.38) of incident hip fracture than women without diabetes. Longer duration of type 2 diabetes was associated with higher incidence, as was use of insulin or oral diabetes medications in women with type 2 diabetes. Furthermore, women who were initially free of diabetes but in whom diabetes developed had a relative risk of hip fracture of 1.60 (1.14-2.25) compared with women who never had diabetes. CONCLUSIONS: Postmenopausal women who have diabetes or in whom diabetes develops are at higher risk for hip fracture than nondiabetic postmenopausal women. Strategies to prevent osteoporosis and/or falling may be especially warranted in women with diabetes.

Menstrual history and risk of hip fractures in postmenopausal women. The Iowa Women's Health Study.

The authors examined prospectively between 1986 and 1997 the relation of irregular menstrual cycles and irregular menstrual bleeding duration earlier in life with risk of hip fracture in 33,434 postmenopausal Iowa women. Over the 318,522 person-years of follow-up, 523 hip fractures were reported. Adjusted for age, smoking, body mass index, waist/hip ratio, and estrogen use, the relative risk of hip fracture in women who reported always having irregular menstrual cycles, compared with women who never had irregular cycles, was 1.36 (95% confidence interval (CI): 1.03, 1.78). Women who reported having irregular menstrual bleeding duration had a 1.40-fold (95% CI: 1.10, 1.78) increased risk of hip fracture compared with women with regular bleeding duration. In addition, women who reported having both irregular menstrual cycles and irregular menstrual bleeding had a 1.82-fold (95% CI: 1.55, 2.15) higher risk of hip fracture than did women who reported neither irregularity. Women who reported only one menstrual disturbance did not have a risk of hip fracture that was significantly different from women who reported no menstrual disturbances. The authors conclude that women with menstrual irregularities are at increased risk of hip fracture, probably because they are estrogen or progesterone deficient.

Whole and refined grain intake and risk of incident postmenopausal breast cancer (United States).

OBJECTIVE: To assess the relation between whole and refined grain intake and risk of incident postmenopausal breast cancer. Findings from case-control studies of whole and refined grain intake and risk of postmenopausal breast cancer have been inconclusive. METHODS: The Iowa Women's Health Study is a prospective cohort study of women initially 55-69 years old that relates diet and other lifestyle factors to cancer risk. After exclusions a total of 29,119 menopausal women who answered a 1986 baseline and a 1989 follow-up questionnaire were followed for 9 years for incident breast cancer. RESULTS: Compared to women who at baseline rarely ate whole grain foods, women who habitually ate whole grain had a healthier lifestyle, including a higher likelihood of prior screening mammography. The multivariate-adjusted risk of incident breast cancer was 20% higher in women in the highest quintile of whole grain intake, compared to women in the lowest quintile of whole grain intake (95% confidence interval 0.95-1.5; p-value for trend = 0.03). No increase in breast cancer risk was found in women who had not undergone screening mammography before 1989; the apparent increase in risk was therefore likely due to increased use of screening mammography. Refined grain intake was not associated with breast cancer risk. CONCLUSION: Consistent with inverse but not statistically significant associations between whole grain intake and breast cancer in case-control studies, both whole and refined grain intakes are unrelated to risk of postmenopausal breast cancer in these Iowa women.

Characteristics of research volunteers for inpatient cocaine studies: focus on selection bias.

In order to investigate the selection bias of subjects for inpatient human cocaine studies, characteristics of 859 potential subjects were examined. Excluded subjects compared with accepted group were more likely to be single and male, currently use drugs other than cocaine, have a history of intravenous cocaine use, and have medical or mental health problems or physical complaints. Subjects who were accepted but did not participate, compared with participants, were likely to spend more money on cocaine. These results suggest that potential subjects who were accepted to our research studies may not accurately represent all potential subjects for several important subject characteristics.