Silvia Alemany

Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences

BACKGROUND The well-established relationship between childhood adversity and psychosis is likely to involve other factors such as genetic variants that can help us to understand why not everyone exposed to adverse events develops psychotic symptoms later in life. AIMS We investigated the influence of childhood abuse and neglect on positive and negative psychotic-like experiences in adulthood and the potential moderating effect of the BDNF-Val66Met polymorphism. METHOD Psychotic-like experiences and childhood adversity were assessed in 533 individuals from the general population. RESULTS Childhood abuse showed a strong independent effect on the positive dimension of psychotic-like experiences (β = 0.16, s.e. = 0.05, P = 0.002). Furthermore, this association was moderated by the BDNF-Val66Met polymorphism (β = 0.27, s.e. = 0.10, P = 0.004). CONCLUSIONS Individuals exposed to childhood abuse are more likely to report positive psychotic-like experiences. Met carriers reported more positive psychotic-like experiences when exposed to childhood abuse than did individuals carrying the Val/Val genotype. Therefore, the observed gene-environment interaction effect may be partially responsible for individual variation in response to childhood abuse.

Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes

To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol‐O‐methyltransferase) gene.

Childhood adversity and psychosis: Examining whether the association is due to genetic confounding using a monozygotic twin differences approach

PURPOSE To test whether the association between childhood adversity and positive and negative psychotic experiences is due to genetic confounding. METHOD Childhood adversity and psychotic experiences were assessed in an ongoing sample of 226 twins from the general population. A monozygotic (MZ) twin differences approach was used to assess possible genetic confounding. RESULTS In the whole sample, childhood adversity was significantly associated with positive (β=45; SE=0.16; P=0.008) and negative psychotic experiences (β=0.77; SE=0.18; P<0.01). Within-pair MZ twin differences in exposure to childhood adversity were significantly associated with differences in positive (β=71; SE=0.29; P=0.016) and negative psychotic experiences (β=98; SE=0.38; P=0.014) in a subsample of 85 MZ twin pairs. CONCLUSIONS Individuals exposed to childhood adversity are more likely to report psychotic experiences. Furthermore, our findings indicate that this association is not due to genetic confounding.

New suggestive genetic loci and biological pathways for attention function in adult attention‐deficit/hyperactivity disorder

Attention deficit is one of the core symptoms of the attention‐deficit/hyperactivity disorder (ADHD). However, the specific genetic variants that may be associated with attention function in adult ADHD remain largely unknown. The present study aimed to identifying SNPs associated with attention function in adult ADHD and tested whether these associations were enriched for specific biological pathways. Commissions, hit‐reaction time (HRT), the standard error of HRT (HRTSE), and intraindividual coefficient variability (ICV) of the Conners Continuous Performance Test (CPT‐II) were assessed in 479 unmedicated adult ADHD individuals. A Genome‐Wide Association Study (GWAS) was conducted for each outcome and, subsequently, gene set enrichment analyses were performed. Although no SNPs reached genome‐wide significance (P < 5E−08), 27 loci showed suggestive evidence of association with the CPT outcomes (P < E−05). The most relevant associated SNP was located in the SORCS2 gene (P = 3.65E−07), previously associated with bipolar disorder (BP), Alzheimer disease (AD), and brain structure in elderly individuals. We detected other genes suggested to be involved in synaptic plasticity, cognitive function, neurological and neuropsychiatric disorders, and smoking behavior such as NUAK1, FGF20, NETO1, BTBD9, DLG2, TOP3B, and CHRNB4. Also, several of the pathways nominally associated with the CPT outcomes are relevant for ADHD such as the ubiquitin proteasome, neurodegenerative disorders, axon guidance, and AD amyloid secretase pathways. To our knowledge, this is the first GWAS and pathway analysis of attention function in patients with persistent ADHD. Overall, our findings reinforce the conceptualization of attention function as a potential endophenotype for studying the molecular basis of adult ADHD.

Gene-environment interaction on cognition: A twin study of childhood maltreatment and COMT variability

The functional variant Val(158)Met in the coding sequence of COMT gene is involved in the modulation of dopamine availability in the prefrontal cortex in both clinical and general population samples. It has been suggested that the interplay between this genotype and early environmental factors could be used to predict the observed variation in cognitive flexibility. However, other genetic variants and environmental factors may confound the association and produce the inconsistent results commonly found in the literature. In the present study we aimed at testing putative interaction mechanisms between childhood maltreatment and COMT genotypic variability that might explain a proportion of the observed variability of cognitive flexibility in the population. Our design was based on a sample of adult monozygotic twins, which allowed us to test these effects free from potential genetic and shared-environmental confounding factors. Results showed that unique environmental effects of childhood maltreatment significantly impacted cognitive performance among Met/Met subjects. Interestingly, the direction of the association indicated that exposure to early stressful experiences was associated with enhanced cognitive flexibility in this genotype group. These results suggest that COMT may operate as a plasticity gene that provides differential cognitive capacity to respond to environmental stressors.

Regional gray matter reductions are associated with genetic liability for anxiety and depression: An MRI twin study

BACKGROUND The influence of genetic and/or environmental factors on the volumetric brain changes observed in subjects affected by anxiety and depression disorders remains unclear. The current study aimed to investigate whether genetic and environmental liabilities make different contributions to abnormalities in gray matter volume (GMV) in anxiety and depression using a concordant and discordant MZ twin pairs design. METHODS Fifty-three magnetic resonance imaging (3T) brain scans were obtained from monozygotic (MZ) twins concordant (6 pairs) and discordant (10 pairs) for lifetime anxiety and depression disorders and from healthy twins (21 subjects). We applied voxel-based morphometry to analyse GMV differences. Concordant affected twins were compared to healthy twins and within-pairs comparisons were performed in the discordant group. RESULTS GMV reductions in bilateral fusiform gyrus and amygdala were observed in concordant affected twins for anxiety and depression compared to healthy twins. No intrapair differences were found in GMV between discordant affected twins and their healthy co-twins. LIMITATIONS The sample size was modest. This might explain why no intrapair differences were found in the discordant MZ twin group. CONCLUSIONS As concordant affected MZ twins are believed to have a particularly high genetic liability for the disorder, our findings suggest that fusiform gyrus and amygdala gray matter reductions are related to a genetic risk for anxiety and depression. Discrepancies in regard to brain abnormalities in anxiety and depression may be related to the admixture of patients with GMV abnormalities mainly accounted for by genetic factors with patients presenting GMV mainly accounted for by environmental factors.

Substantial Genetic Link Between IQ and Working Memory: Implications for Molecular Genetic Studies on Schizophrenia. The European Twin Study of Schizophrenia (EUTwinsS)

While evidence is accumulating to support specific neurocognitive deficits as putative endophenotypes for schizophrenia, the heritability of these deficits in healthy subjects and whether they share common genetic influences, is not well established. In the present study, 529 healthy adult twins from two centers within the European Twin Study Network on Schizophrenia (EUTwinsS) were assessed on two domains that are consistently found to be particularly compromised in schizophrenia. Specifically, Intellectual Quotient Score (IQ) and the Letter–Number Sequencing Test (LNS), a measure of working memory, were measured in all twins. Latent variable components were explored through structural equation modeling, and common genetic underpinnings were examined using bivariate analyses. Results showed that the phenotypic correlation between IQ and working memory was almost entirely attributed to shared genetic variance (95.5%). We discuss the potential use of a combined measure of IQ and working memory to improve the power of molecular studies in detecting the genetic mechanisms underlying schizophrenia.

Research Letter: Childhood trauma and the rs1360780 SNP of FKBP5 gene in psychosis: a replication in two general population samples

Ministry of Science and Innovation. SAF2008-05674-C03-00 SAF2008-05674-C03-03 PI12/00018 PNSD2008-I090 PNSD2009-I019. Institute of Health Carlos III CIBER of Mental Health (CIBERSAM) Comissionat per a Universitats i Recerca, DIUE, Generalitat de Catalunya 2014SGR1636 ERA-NET NEURON PIM2010-ERN-00642 Fundacio Caixa Castello-Bancaixa P1.1B2010-40 P1.1B2011-47

Birth Weight, Working Memory and Epigenetic Signatures in IGF2 and Related Genes: A MZ Twin Study

Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2) and IGF2BP1-3 (IGF2-binding proteins 1-3) were examined in a sample consisting of 34 adult monozygotic (MZ) twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW) and adult working memory (WM) performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.

Genetic origin of the relationship between parental negativity and behavior problems from early childhood to adolescence: a longitudinal genetically sensitive study.

Little is known about how genetic and environmental factors contribute to the association between parental negativity and behavior problems from early childhood to adolescence. The current study fitted a cross-lagged model in a sample consisting of 4,075 twin pairs to explore (a) the role of genetic and environmental factors in the relationship between parental negativity and behavior problems from age 4 to age 12, (b) whether parent-driven and child-driven processes independently explain the association, and (c) whether there are sex differences in this relationship. Both phenotypes showed substantial genetic influence at both ages. The concurrent overlap between them was mainly accounted for by genetic factors. Causal pathways representing stability of the phenotypes and parent-driven and child-driven effects significantly and independently account for the association. Significant but slight differences were found between males and females for parent-driven effects. These results were highly similar when general cognitive ability was added as a covariate. In summary, the longitudinal association between parental negativity and behavior problems seems to be bidirectional and mainly accounted for by genetic factors. Furthermore, child-driven effects were mainly genetically mediated, and parent-driven effects were a function of both genetic and shared-environmental factors.