The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r g ¼ À 0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth.
Laboratory animal and human subject studies report that the amygdala is a critical brain structure that supports the acquisition and expression of conditional fear. Recent functional neuroimaging studies in humans have reported that activity in this region is closely related to the behavioral expression of conditional skin conductance responses (SCR). However, SCR waveforms following conditional stimulus (CS) presentation contain both early period and late period responses that may differ with respect to underlying central processes. It is not known whether amygdala activity corresponds to the expression of early conditonal responses (CRs) that occur shortly following CS onset or late CRs that closely precede UCS onset. The present study used event-related functional magnetic resonance imaging and concurrent skin conductance measurements to determine whether amygdala activity is more closely related to the expression of early or late period CRs. Increased amygdala activity was detected during the formation of early, but not late period CRs. Additionally, this pattern of amygdala activity did not dissipate, but persisted into late stages of the experiment. These findings are consistent with the idea that amygdala responding is critically involved in the generation of CRs formed shortly following CS onset.
Cross-assortative mating for ASD and ADHD does not form an explanation for the frequent co-occurrence of these disorders within families. Given that parental ADHD is predictive of offspring' ASD but not vice versa, risk factors underlying ASD may overlap to a larger degree with risk factors underlying ADHD than vice versa. However, future research is needed to clarify this issue.
These family-genetic findings suggest that the comorbid condition BPD+ANX may be a distinct clinical entity. More work is needed to evaluate whether the presence of comorbid ANX may be a marker of very early onset BPD.
Introduction
The role of the serotonin transporter gene polymorphism 5-HTTLPR in attention-deficit/hyperactivity disorder (ADHD) is unclear. Heterogeneity of findings may be explained by gene-environment interactions (GxE), as it has been suggested that S-allele carriers are more reactive to psychosocial stress than L-allele homozygotes. This study aimed to investigate whether 5-HTTLPR genotype moderates effects of stress on ADHD in a multi-site prospective ADHD cohort study.
Methods
5-HTTLPR genotype, as well as the number of stressful life events in the past five years and ongoing long-term difficulties, were determined in 671 adolescents and young adults with ADHD, their siblings, and healthy controls (57.4% male, average age 17.3 years). Linear mixed models, accounting for family relatedness, were applied to investigate the effects of genotype, experienced stress, and their interaction on ADHD severity at time point T2, while controlling for ADHD severity at T1 (mean follow-up time 5.9 years) and for comorbid internalizing problems at T2.
Results
The interaction between genotype and stress significantly predicted ADHD severity at T2 (p=.006), which was driven by the effect on hyperactivity-impulsivity (p=.004). Probing of the interaction effect made clear that S-allele carriers had a significantly more positive correlation between stress and ADHD severity than L-allele homozygotes.
Conclusion
The results show that the interaction between 5-HTTLPR and stress is a mechanism involved particularly in the hyperactivity/impulsivity dimension of ADHD, and that this is independent of comorbid internalizing problems. Further research into the neurobiological mechanisms underlying this interaction effect is warranted.
Social withdrawal and social anxiety are believed to have a bidirectional influence on one another, but it is unknown if their relationship is bidirectional, especially within person, and if peer experiences influence this relationship. We investigated temporal sequencing and the strength of effects between social withdrawal and social anxiety, and the roles of peer victimization and acceptance in the pathways. Participants were 2,772 adolescents from the population-based and clinically referred cohorts of the Tracking Adolescents' Individual Lives Survey. Self- and parent-reported withdrawal, and self-reported social anxiety, peer victimization, and perceived peer acceptance were assessed at 11, 13, and 16 years. Random-intercept cross-lagged panel models were used to investigate within-person associations between these variables. There was no feedback loop between withdrawal and social anxiety. Social withdrawal did not predict social anxiety at any age. Social anxiety at 11 years predicted increased self-reported withdrawal at 13 years. Negative peer experiences predicted increased self- and parent-reported withdrawal at 13 years and increased parent-reported withdrawal at 16 years. In turn, self-reported withdrawal at 13 years predicted negative peer experiences at 16 years. In conclusion, adolescents became more withdrawn when they became more socially anxious or experienced greater peer problems, and increasing withdrawal predicted greater victimization and lower acceptance.
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