The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Prevalence and course of sexual relationship difficulties in recovered and non-recovered patients with borderline personality disorder over 16years of prospective follow-up

Although borderline patients experience a wide range of sexual problems, including promiscuity, there is less evidence documenting their sexual relationship difficulties. This study had two aims. The first was to examine the prevalence of these difficulties (i.e. avoidance of sex and being symptomatic after sex) over 16years of prospective follow-up among recovered and non-recovered patients with borderline personality disorder (BPD). The second was to determine time-to-remission, recurrence and new onset of these sexual relationship difficulties. The sexual relationship difficulties of 290 patients meeting both DIB-R and DSM-III-R criteria for BPD were assessed at baseline using the Abuse History Interview and reassessed every two years over eight waves of prospective follow-up. The prevalence of sexual relationship difficulties declined significantly over time for both groups of patients, while remaining significantly more common among non-recovered patients. By 16-year follow-up, over 95% of each group achieved remission for both types of difficulties. Recurrences of avoidance of sex were significantly more common in non-recovered patients. Non-recovered patients had higher rates of new onsets compared to recovered patients for each type of sexual relationship difficulty. Taken together, the results suggest that sexual relationship difficulties are not chronic for those with BPD regardless of recovery status. Copyright (c) 2016 John Wiley & Sons, Ltd

Description and prediction of the income status of borderline patients over 10 years of prospective follow‐up

BackgroundResearch shows that individuals suffering from borderline personality disorder are economically disadvantaged, but longitudinal data is lacking. AimThis study examined the income of borderline personality disorder (BPD) patients and axis II comparison subjects over 10years of follow-up and assessed predictors of income among BPD patients. MethodData on income was obtained for 264 BPD patients and 63 axis II comparison subjects at 6-year follow-up and for surviving patients at five follow-up waves. Baseline and time-varying predictors of income were assessed using information from interviews and self-report measures. ResultsRegardless of diagnosis, a greater proportion of people shifted into the higher income groups over time. Being in a higher income group was more likely to happen and happened more rapidly for axis II comparison subjects than for BPD patients. Results regarding the BPD patients indicated that childhood emotional, verbal and/or physical abuse were associated with a greater likelihood of being in a lower income group, whereas years of education and a higher IQ were associated with a greater likelihood of being in a higher income group. ConclusionBorderline personality disorder (BPD) patients show enduring lowered economic functioning. Their economic functioning seems to be negatively affected by childhood emotional, verbal and/or physical abuse but positively affected by years of education and IQ. Copyright (c) 2016 John Wiley & Sons, Ltd