Anke R. Hammerschlag

Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia

Objective: We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations. Methods: In this case-control study, 75 healthy individuals (aged 20–70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex. Results: Although carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found. Conclusions: This study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.

Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10−8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10−6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10−6). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10−29). These findings provide new insight into the genetic architecture of intelligence.

Gene expression in major depressive disorder

The search for genetic variants underlying major depressive disorder (MDD) has not yet provided firm leads to its underlying molecular biology. A complementary approach is to study gene expression in relation to MDD. We measured gene expression in peripheral blood from 1848 subjects from The Netherlands Study of Depression and Anxiety. Subjects were divided into current MDD (N=882), remitted MDD (N=635) and control (N=331) groups. MDD status and gene expression were measured again 2 years later in 414 subjects. The strongest gene expression differences were between the current MDD and control groups (129 genes at false-discovery rate, FDR<0.1). Gene expression differences across MDD status were largely unrelated to antidepressant use, inflammatory status and blood cell counts. Genes associated with MDD were enriched for interleukin-6 (IL-6)-signaling and natural killer (NK) cell pathways. We identified 13 gene expression clusters with specific clusters enriched for genes involved in NK cell activation (downregulated in current MDD, FDR=5.8 × 10−5) and IL-6 pathways (upregulated in current MDD, FDR=3.2 × 10−3). Longitudinal analyses largely confirmed results observed in the cross-sectional data. Comparisons of gene expression results to the Psychiatric Genomics Consortium (PGC) MDD genome-wide association study results revealed overlap with DVL3. In conclusion, multiple gene expression associations with MDD were identified and suggest a measurable impact of current MDD state on gene expression. Identified genes and gene clusters are enriched with immune pathways previously associated with the etiology of MDD, in line with the immune suppression and immune activation hypothesis of MDD.

Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits

Persistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-based association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes associated with insomnia complaints, with the associations for one locus and five genes supported by joint analysis with an independent sample (n = 7,565). Our top association (MEIS1, P < 5 × 10−8) has previously been implicated in restless legs syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 exhibits pleiotropy for insomnia and RLS and show that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup within the cases. Sex-specific analyses suggest that there are different genetic architectures between the sexes in addition to shared genetic factors. We show substantial positive genetic correlation of insomnia complaints with internalizing personality traits and metabolic traits and negative correlation with subjective well-being and educational attainment. These findings provide new insight into the genetic architecture of insomnia.

Gene expression in major depressive disorder: ERRATUM

Correction to: Molecular Psychiatry advance online publication, 26 May 2015; doi:10.1038/mp.2015.57 Following publication of the above article, the authors noticed that the Supplementary Figure legends were not published with the paper. The legends accompany this erratum. In addition, the Supplementary Tables were originally presented as PDF files.

Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)

Attention Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood-onset neuropsychiatric disorders. Despite high heritability estimates, genome-wide association studies (GWAS) have failed to find significant genetic associations, likely due to the polygenic character of ADHD. Nevertheless, genetic studies suggested the involvement of several processes important for synaptic function. Therefore, we applied a functional gene-set analysis to formally test whether synaptic functions are associated with ADHD. Gene-set analysis tests the joint effect of multiple genetic variants in groups of functionally related genes. This method provides increased statistical power compared to conventional GWAS. We used data from the Psychiatric Genomics Consortium including 896 ADHD cases and 2455 controls, and 2064 parent-affected offspring trios, providing sufficient statistical power to detect gene sets representing a genotype relative risk of at least 1.17. Although all synaptic genes together showed a significant association with ADHD, this association was not stronger than that of randomly generated gene sets matched for same number of genes. Further analyses showed no association of specific synaptic function categories with ADHD after correction for multiple testing. Given current sample size and gene sets based on current knowledge of genes related to synaptic function, our results do not support a major role for common genetic variants in synaptic genes in the etiology of ADHD.

Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior

Importance Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. Objectives To estimate the single-nucleotide polymorphism–based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Design, Setting, and Participants Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). Main Outcome and Measures This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. Results The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = –0.52, P = .005) was detected. Conclusions and Relevance The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.

A Population-Based Imaging Genetics Study of Inattention/Hyperactivity: Basal Ganglia and Genetic Pathways.

OBJECTIVE Although attention-deficit/hyperactivity disorder (ADHD) is 1 of the most common neurodevelopmental disorders, little is known about the neurobiology. Clinical studies suggest basal ganglia morphology plays a role. Furthermore, hyperactivity/impulsivity symptoms have recently been linked to genetic pathways involved in dopamine/norepinephrine and serotonin neurotransmission and neuritic outgrowth. We aimed to assess the association between ADHD symptoms, basal ganglia volume, and the 3 proposed genetic pathways in a pediatric population-based sample. With this, we aimed to investigate the generalizability of earlier clinical findings to the general population. METHOD This study included a population-based sample of 1,871 children with data on ADHD symptoms and genetic data, and 344 children with additional neuroimaging data. Regression analyses between ADHD symptom severity and volumetric data of the basal ganglia were performed. Also, gene-set analyses investigating the association between both ADHD symptom severity and basal ganglia volume with the dopamine/norepinephrine, serotonin, and neuritic outgrowth pathways were performed. RESULTS More inattention and hyperactivity/impulsivity symptoms were associated with a smaller volume of the putamen (β = -0.13, p = .034), which was regarded as trend-level after correction for multiple testing. Stratified analyses showed a stronger putamen-hyperactivity association in children with clinical scores, although a similar trend was visible in the nonclinical subsample. The genetic pathways were not related to either ADHD symptoms or basal ganglia volume. CONCLUSION ADHD symptoms were marginally related to putamen volume in our population-based sample. We found no evidence for a role of dopamine/norepinephrine, serotonin, or neuritic outgrowth genetic pathways in ADHD symptom severity.

Genome-wide Analysis of Insomnia (N=1,331,010) Identifies Novel Loci and Functional Pathways

Insomnia is the second-most prevalent mental disorder, with no sufficient treatment available. Despite a substantial role of genetic factors, only a handful of genes have been implicated and insight into the associated neurobiological pathways remains limited. Here, we use an unprecedented large genetic association sample (N=1,331,010) to allow detection of a substantial number of genetic variants and gain insight into biological functions, cell types and tissues involved in insomnia. We identify 202 genome-wide significant loci implicating 956 genes through positional, eQTL and chromatin interaction mapping. We show involvement of the axonal part of neurons, of specific cortical and subcortical tissues, and of two specific cell-types in insomnia: striatal medium spiny neurons and hypothalamic neurons. These cell-types have been implicated previously in the regulation of reward processing, sleep and arousal in animal studies, but have never been genetically linked to insomnia in humans. We found weak genetic correlations with other sleep-related traits, but strong genetic correlations with psychiatric and metabolic traits. Mendelian randomization identified causal effects of insomnia on specific psychiatric and metabolic traits. Our findings reveal key brain areas and cells implicated in the neurobiology of insomnia and its related disorders, and provide novel targets for treatment.

Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways

Neuroticism is an important risk factor for psychiatric traits, including depression1, anxiety2,3, and schizophrenia4–6. At the time of analysis, previous genome-wide association studies7–12 (GWAS) reported 16 genomic loci associated to neuroticism10–12. Here we conducted a large GWAS meta-analysis (n = 449,484) of neuroticism and identified 136 independent genome-wide significant loci (124 new at the time of analysis), which implicate 599 genes. Functional follow-up analyses showed enrichment in several brain regions and involvement of specific cell types, including dopaminergic neuroblasts (P = 3.49 × 10−8), medium spiny neurons (P = 4.23 × 10−8), and serotonergic neurons (P = 1.37 × 10−7). Gene set analyses implicated three specific pathways: neurogenesis (P = 4.43 × 10−9), behavioral response to cocaine processes (P = 1.84 × 10−7), and axon part (P = 5.26 × 10−8). We show that neuroticism’s genetic signal partly originates in two genetically distinguishable subclusters13 (‘depressed affect’ and ‘worry’), suggesting distinct causal mechanisms for subtypes of individuals. Mendelian randomization analysis showed unidirectional and bidirectional effects between neuroticism and multiple psychiatric traits. These results enhance neurobiological understanding of neuroticism and provide specific leads for functional follow-up experiments.A meta-analysis of genome-wide association studies for neuroticism identifies novel loci, pathways and potential drug targets. Further analysis implicates specific brain regions and evaluates genetic overlap with other neuropsychiatric traits.