Discordant associations of educational attainment with ASD and ADHD implicate a polygenic form of pleiotropy.

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex co-occurring neurodevelopmental conditions. Their genetic architectures reveal striking similarities but also differences, including strong, discordant polygenic associations with educational attainment (EA). To study genetic mechanisms that present as ASD-related positive and ADHD-related negative genetic correlations with EA, we carry out multivariable regression analyses using genome-wide summary statistics (N = 10,610-766,345). Our results show that EA-related genetic variation is shared across ASD and ADHD architectures, involving identical marker alleles. However, the polygenic association profile with EA, across shared marker alleles, is discordant for ASD versus ADHD risk, indicating independent effects. At the single-variant level, our results suggest either biological pleiotropy or co-localisation of different risk variants, implicating MIR19A/19B microRNA mechanisms. At the polygenic level, they point to a polygenic form of pleiotropy that contributes to the detectable genome-wide correlation between ASD and ADHD and is consistent with effect cancellation across EA-related regions

Genome-wide analyses suggest parallel selection for universal traits may eclipse local environmental selection in a highly mobile carnivore

Ecological and environmental heterogeneity can produce genetic differentiation in highly mobile species. Accordingly, local adaptation may be expected across comparatively short distances in the presence of marked environmental gradients. Within the European continent, wolves (Canis lupus) exhibit distinct north-south population differentiation. We investigated more than 67-K single nucleotide polymorphism (SNP) loci for signatures of local adaptation in 59 unrelated wolves from four previously identified population clusters (northcentral Europe n=32, Carpathian Mountains n=7, Dinaric-Balkan n=9, Ukrainian Steppe n=11). Our analyses combined identification of outlier loci with findings from genome-wide association study of individual genomic profiles and 12 environmental variables. We identified 353 candidate SNP loci. We examined the SNP position and neighboring megabase (1Mb, one million bases) regions in the dog (C. lupus familiaris) genome for genes potentially under selection, including homologue genes in other vertebrates. These regions included functional genes for, for example, temperature regulation that may indicate local adaptation and genes controlling for functions universally important for wolves, including olfaction, hearing, vision, and cognitive functions. We also observed strong outliers not associated with any of the investigated variables, which could suggest selective pressures associated with other unmeasured environmental variables and/or demographic factors. These patterns are further supported by the examination of spatial distributions of the SNPs associated with universally important traits, which typically show marked differences in allele frequencies among population clusters. Accordingly, parallel selection for features important to all wolves may eclipse local environmental selection and implies long-term separation among population clusters.201

Investigating causality between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization

Attention-deficit hyperactivity disorder (ADHD) has consistently been associated with substance use, but the nature of this association is not fully understood. To inform intervention development and public health messages, a vital question is whether there are causal pathways from ADHD to substance use and/or vice versa. We applied bidirectional Mendelian randomization, using summary-level data from the largest available genome-wide association studies (GWAS) on ADHD, smoking (initiation, cigarettes per day, cessation, and a compound measure of lifetime smoking), alcohol use (drinks per week, alcohol problems, and alcohol dependence), cannabis use (initiation), and coffee consumption (cups per day). Genetic variants robustly associated with the “exposure” were selected as instruments and identified in the “outcome” GWAS. Effect estimates from individual genetic variants were combined with inverse-variance weighted regression and five sensitivity analyses (weighted median, weighted mode, MR-Egger, generalized summary data–based MR, and Steiger filtering). We found evidence that liability to ADHD increases likelihood of smoking initiation and heaviness of smoking among smokers, decreases likelihood of smoking cessation, and increases likelihood of cannabis initiation. There was weak evidence that liability to ADHD increases alcohol dependence risk but not drinks per week or alcohol problems. In the other direction, there was weak evidence that smoking initiation increases ADHD risk, but follow-up analyses suggested a high probability of horizontal pleiotropy. There was no clear evidence of causal pathways between ADHD and coffee consumption. Our findings corroborate epidemiological evidence, suggesting causal pathways from liability to ADHD to smoking, cannabis use, and, tentatively, alcohol dependence. Further work is needed to explore the exact mechanisms mediating these causal effects

North-south differentiation and a region of high diversity in European wolves (Canis lupus)

European wolves (Canis lupus) show population genetic structure in the absence of geographic barriers, and across relatively short distances for this highly mobile species. Additional information on the location of and divergence between population clusters is required, particularly because wolves are currently recolonizing parts of Europe. We evaluated genetic structure in 177 wolves from 11 countries using over 67K single nucleotide polymorphism (SNP) loci. The results supported previous findings of an isolated Italian population with lower genetic diversity than that observed across other areas of Europe. Wolves from the remaining countries were primarily structured in a north-south axis, with Croatia, Bulgaria, and Greece (Dinaric-Balkan) differentiated from northcentral wolves that included individuals from Finland, Latvia, Belarus, Poland and Russia. Carpathian Mountain wolves in central Europe had genotypes intermediate between those identified in northcentral Europe and the Dinaric-Balkan cluster. Overall, individual genotypes from northcentral Europe suggested high levels of admixture. We observed high diversity within Belarus, with wolves from western and northern Belarus representing the two most differentiated groups within northcentral Europe. Our results support the presence of at least three major clusters (Italy, Carpathians, Dinaric-Balkan) in southern and central Europe. Individuals from Croatia also appeared differentiated from wolves in Greece and Bulgaria. Expansion from glacial refugia, adaptation to local environments, and human-related factors such as landscape fragmentation and frequent killing of wolves in some areas may have contributed to the observed patterns. Our findings can help inform conservation management of these apex predators and the ecosystems of which they are part

Identification of the BRD1 interaction network and its impact on mental disorder risk

BACKGROUND: The bromodomain containing 1 (BRD1) gene has been implicated with transcriptional regulation, brain development, and susceptibility to schizophrenia and bipolar disorder. To advance the understanding of BRD1 and its role in mental disorders, we characterized the protein and chromatin interactions of the BRD1 isoforms, BRD1-S and BRD1-L. METHODS: Stable human cell lines expressing epitope tagged BRD1-S and BRD1-L were generated and used as discovery systems for identifying protein and chromatin interactions. Protein-protein interactions were identified using co-immunoprecipitation followed by mass spectrometry and chromatin interactions were identified using chromatin immunoprecipitation followed by next generation sequencing. Gene expression profiles and differentially expressed genes were identified after upregulating and downregulating BRD1 expression using microarrays. The presented functional molecular data were integrated with human genomic and transcriptomic data using available GWAS, exome-sequencing datasets as well as spatiotemporal transcriptomic datasets from the human brain. RESULTS: We present several novel protein interactions of BRD1, including isoform-specific interactions as well as proteins previously implicated with mental disorders. By BRD1-S and BRD1-L chromatin immunoprecipitation followed by next generation sequencing we identified binding to promoter regions of 1540 and 823 genes, respectively, and showed correlation between BRD1-S and BRD1-L binding and regulation of gene expression. The identified BRD1 interaction network was found to be predominantly co-expressed with BRD1 mRNA in the human brain and enriched for pathways involved in gene expression and brain function. By interrogation of large datasets from genome-wide association studies, we further demonstrate that the BRD1 interaction network is enriched for schizophrenia risk. CONCLUSION: Our results show that BRD1 interacts with chromatin remodeling proteins, e.g. PBRM1, as well as histone modifiers, e.g. MYST2 and SUV420H1. We find that BRD1 primarily binds in close proximity to transcription start sites and regulates expression of numerous genes, many of which are involved with brain development and susceptibility to mental disorders. Our findings indicate that BRD1 acts as a regulatory hub in a comprehensive schizophrenia risk network which plays a role in many brain regions throughout life, implicating e.g. striatum, hippocampus, and amygdala at mid-fetal stages. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-016-0308-x) contains supplementary material, which is available to authorized users

Robustness of genome-wide scanning using archived dried blood spot samples as a DNA source

<p>Abstract</p> <p>Background</p> <p>The search to identify disease-susceptible genes requires access to biological material from numerous well-characterized subjects. Archived residual dried blood spot (DBS) samples, also known as Guthrie cards, from national newborn screening programs may provide a DNA source for entire populations. Combined with clinical information from medical registries, DBS samples could provide a rich source for productive research. However, the amounts of DNA which can be extracted from these precious samples are minute and may be prohibitive for numerous genotypings. Previously, we demonstrated that DBS DNA can be whole-genome amplified and used for reliable genetic analysis on different platforms, including genome-wide scanning arrays. However, it remains unclear whether this approach is workable on a large sample scale. We examined the robustness of using DBS samples for whole-genome amplification following genome-wide scanning, using arrays from Illumina and Affymetrix.</p> <p>Results</p> <p>This study is based on 4,641 DBS samples from the Danish Newborn Screening Biobank, extracted for three separate genome-wide association studies. The amount of amplified DNA was significantly (P < 0.05) affected by the year of storage and storage conditions. Nine (0.2%) DBS samples failed whole-genome amplification. A total of 4,586 (98.8%) samples met our criterion of success of a genetic call-rate above 97%. The three studies used different arrays, with mean genotyping call-rates of 99.385% (Illumina Infinium Human610-Quad), 99.722% (Illumina Infinium HD HumanOmni1-Quad), and 99.206% (Affymetrix Axiom Genome-Wide CEU). We observed a concordance rate of 99.997% in the 38 methodological replications, and 99.999% in the 27 technical replications. Handling variables such as time of storage, storage conditions and type of filter paper were shown too significantly (P < 0.05) affect the genotype call-rates in some of the arrays, although the effect was minimal.</p> <p>Conclusion</p> <p>Our study indicates that archived DBS samples from the Danish Newborn Screening Biobank represent a reliable resource of DNA for whole-genome amplification and subsequent genome-wide association studies. With call-rates equivalent to high quality DNA samples, our results point to new opportunities for using the neonatal biobanks available worldwide in the hunt for genetic components of disease.</p

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10-10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior

Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder

Analyses of the polygenic architecture of childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder (ADHD) in a Danish population-based case-cohort sample identify differences among ADHD subgroups with respect to common and rare variants. Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset in childhood (childhood ADHD); two-thirds of affected individuals continue to have ADHD in adulthood (persistent ADHD), and sometimes ADHD is diagnosed in adulthood (late-diagnosed ADHD). We evaluated genetic differences among childhood (n = 14,878), persistent (n = 1,473) and late-diagnosed (n = 6,961) ADHD cases alongside 38,303 controls, and rare variant differences in 7,650 ADHD cases and 8,649 controls. We identified four genome-wide significant loci for childhood ADHD and one for late-diagnosed ADHD. We found increased polygenic scores for ADHD in persistent ADHD compared with the other two groups. Childhood ADHD had higher genetic overlap with hyperactivity and autism compared with late-diagnosed ADHD and the highest burden of rare protein-truncating variants in evolutionarily constrained genes. Late-diagnosed ADHD had a larger genetic overlap with depression than childhood ADHD and no increased burden in rare protein-truncating variants. Overall, these results suggest a genetic influence on age at first ADHD diagnosis, persistence of ADHD and the different comorbidity patterns among the groups.Peer reviewe

Genome-wide association study of school grades identifies genetic overlap between language ability, psychopathology and creativity

Cognitive functions of individuals with psychiatric disorders differ from that of the general population. Such cognitive differences often manifest early in life as differential school performance and have a strong genetic basis. Here we measured genetic predictors of school performance in 30,982 individuals in English, Danish and mathematics via a genome-wide association study (GWAS) and studied their relationship with risk for six major psychiatric disorders. When decomposing the school performance into math and language-specific performances, we observed phenotypically and genetically a strong negative correlation between math performance and risk for most psychiatric disorders. But language performance correlated positively with risk for certain disorders, especially schizophrenia, which we replicate in an independent sample (n = 4547). We also found that the genetic variants relating to increased risk for schizophrenia and better language performance are overrepresented in individuals involved in creative professions (n = 2953) compared to the general population (n = 164,622). The findings together suggest that language ability, creativity and psychopathology might stem from overlapping genetic roots.Peer reviewe

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10-10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior