Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease.

Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.

DeepGWAS: Enhance GWAS Signals for Neuropsychiatric Disorders via Deep Neural Network.

Genetic dissection of neuropsychiatric disorders can potentially reveal novel therapeutic targets. While genome-wide association studies (GWAS) have tremendously advanced our understanding, we approach a sample size bottleneck (i.e.

Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis.

Background: It remains unknown why ~30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations of treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we identified schizophrenia-associated CNVs in patients with treatment-resistant psychotic symptoms and then compared the prevalence of these CNVs to previously published schizophrenia cases not selected for treatment resistance.

Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia.

Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia.

The impact of educational attainment, intelligence and intellectual disability on schizophrenia: a Swedish population-based register and genetic study.

Schizophrenia (SCZ) is highly heterogenous and no subtypes characterizing treatment response or longitudinal course well. Cognitive impairment is a core clinical feature of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive traits is complex, with limited studies of comprehensive epidemiological and genomic evidence.

Elevated common variant genetic risk for tourette syndrome in a densely-affected pedigree.

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pedigree using a systematic genomic approach.

Genome-Wide Association Analysis of Neonatal White Matter Microstructure.

A better understanding of genetic influences on early white matter development could significantly advance our understanding of neurological and psychiatric conditions characterized by altered integrity of axonal pathways. We conducted a genome-wide association study (GWAS) of diffusion tensor imaging (DTI) phenotypes in 471 neonates. We used a hierarchical functional principal regression model (HFPRM) to perform joint analysis of 44 fiber bundles.

Treatment-resistant psychotic symptoms and early-onset dementia: A case report of the 3q29 deletion syndrome.

The 3q29 deletion is a rare copy number variant associated with neurodevelopmental and psychiatric disorders, including a >40-fold increased risk for schizophrenia. Current understanding of the clinical phenotype is derived primarily from published cases of patients in childhood or early adolescence. Symptoms include mild to moderate learning disability, developmental delay, facial dysmorphism, microcephaly, ocular disorders, and gastrointestinal abnormalities.

Association test using Copy Number Profile Curves (CONCUR) enhances power in rare copy number variant analysis.

Copy number variants (CNVs) are the gain or loss of DNA segments in the genome that can vary in dosage and length. CNVs comprise a large proportion of variation in human genomes and impact health conditions. To detect rare CNV associations, kernel-based methods have been shown to be a powerful tool due to their flexibility in modeling the aggregate CNV effects, their ability to capture effects from different CNV features, and their accommodation of effect heterogeneity.

Treatment-resistant psychotic symptoms and the 15q11.2 BP1-BP2 (Burnside-Butler) deletion syndrome: case report and review of the literature.

The 15q11.2 BP1-BP2 (Burnside-Butler) deletion is a rare copy number variant impacting four genes (NIPA1, NIPA2, CYFIP1, and TUBGCP5), and carries increased risks for developmental delay, intellectual disability, and neuropsychiatric disorders (attention-deficit/hyperactivity disorder, autism, and psychosis). In this case report (supported by extensive developmental information and medication history), we present the complex clinical portrait of a 44-year-old woman with 15q11.

Characterization of Single Gene Copy Number Variants in Schizophrenia.

Background: Genetic studies of schizophrenia have implicated numerous risk loci including several copy number variants (CNVs) of large effect and hundreds of loci of small effect. In only a few cases has a specific gene been clearly identified. Rare CNVs affecting a single gene offer a potential avenue to discovering schizophrenia risk genes.

Correction: Common-variant associations with fragile X syndrome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%.

The genomics of major psychiatric disorders in a large pedigree from Northern Sweden.

We searched for genetic causes of major psychiatric disorders (bipolar disorder, schizoaffective disorder, and schizophrenia) in a large, densely affected pedigree from Northern Sweden that originated with three pairs of founders born around 1650. We applied a systematic genomic approach to the pedigree via karyotyping (N = 9), genome-wide SNP arrays (N = 418), whole-exome sequencing (N = 26), and whole-genome sequencing (N = 10). Comprehensive analysis did not identify plausible variants of strong effect.

A randomized approach to speed up the analysis of large-scale read-count data in the application of CNV detection.

Background: The application of high-throughput sequencing in a broad range of quantitative genomic assays (e.g., DNA-seq, ChIP-seq) has created a high demand for the analysis of large-scale read-count data.

Genome-wide association analysis identifies common variants influencing infant brain volumes.

Genome-wide association studies (GWAS) of adolescents and adults are transforming our understanding of how genetic variants impact brain structure and psychiatric risk, but cannot address the reality that psychiatric disorders are unfolding developmental processes with origins in fetal life. To investigate how genetic variation impacts prenatal brain development, we conducted a GWAS of global brain tissue volumes in 561 infants. An intronic single-nucleotide polymorphism (SNP) in IGFBP7 (rs114518130) achieved genome-wide significance for gray matter volume (P=4.