A blended genome and exome sequencing method captures genetic variation in an unbiased, high-quality, and cost-effective manner.

We deployed the Blended Genome Exome (BGE), a DNA library blending approach that generates low pass whole genome (1-4× mean depth) and deep whole exome (30-40× mean depth) data in a single sequencing run. This technology is cost-effective, empowers most genomic discoveries possible with deep whole genome sequencing, and provides an unbiased method to capture the diversity of common SNP variation across the globe. To evaluate this new technology at scale, we applied BGE to sequence >53,000 samples from the Populations Underrepresented in Mental Illness Associations Studies (PUMAS) Project, which included participants across African, African American, and Latin American populations.

Biological Insights from Schizophrenia-associated Loci in Ancestral Populations.

Large-scale genome-wide association studies of schizophrenia have uncovered hundreds of associated loci but with extremely limited representation of African diaspora populations. We surveyed electronic health records of 200,000 individuals of African ancestry in the Million Veteran and All of Us Research Programs, and, coupled with genotype-level data from four case-control studies, realized a combined sample size of 13,012 affected and 54,266 unaffected persons. Three genome-wide significant signals - near , , and - are the first to be independently identified in populations of predominantly African ancestry.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 17 likely causal SNPs for BD.

Cultured Mesenchymal Cells from Nasal Turbinate as a Cellular Model of the Neurodevelopmental Component of Schizophrenia Etiology.

The study of neurodevelopmental molecular mechanisms in schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously utilized cell lines with neural progenitor properties (CNON) derived from the superior or middle turbinates of patients with schizophrenia and control groups to study schizophrenia-specific gene expression. In this study, we analyzed single-cell RNA seq data from two CNON cell lines (one derived from an individual with schizophrenia (SCZ) and the other from a control group) and two biopsy samples from the middle turbinate (MT) (also from an individual with SCZ and a control).

Traumatic events in childhood and adulthood in a diverse-ancestry sample and their role in bipolar disorder.

We examined the presence of adverse events in both childhood and adulthood and the prevalence of PTSD in individuals with Bipolar Disorder (BD). There were 191 adults diagnosed with BD Type I and 924 controls, of predominantly African Ancestry (AA). All were administered the GPC-Screening Tool and the BD group the DIPAD.

Cultured Mesenchymal Cells from Nasal Turbinate as a Cellular Model of the Neurodevelopmental Component of Schizophrenia Etiology.

Study of the neurodevelopmental molecular mechanisms of schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously used cell lines with neural progenitor properties (CNON) derived from superior or middle turbinates of patients with schizophrenia and control groups to study gene expression specific to schizophrenia. In this study, we compared single cell-RNA seq data from two CNON cell lines, one derived from an individual with schizophrenia (SCZ) and the other from a control group, with two biopsy samples from the middle turbinate (MT), also from an individual with SCZ and a control.

Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear.

Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance.

Risk for alcohol use problems in severe mental illness: Interactions with sex and racial/ethnic minority status.

Background: Alcohol use disorder (AUD) is exceedingly common among individuals with bipolar disorder and schizophrenia. However, studies on alcohol use in psychiatric illness rely largely on population surveys with limited representation of severe mental illness (SMI); schizophrenia and bipolar disorder.

Methods: Using data from the Genomic Psychiatry Cohort (GPC) (Pato MT, 2013), associations of bipolar disorder and schizophrenia with alcohol use problems were examined in a diverse US based sample, considering the influence of self-described race (African Ancestry (AA), European Ancestry (EA), or Latinx Ancestry (LA)), sex, and tobacco use.

Linking nervous and immune systems in psychiatric illness: A meta-analysis of the kynurenine pathway.

Tryptophan is an essential amino acid absorbed by the gut depending on a homoeostatic microbiome. Up to 95% of unbound tryptophan is converted into tryptophan catabolites (TRYCATs) through the kynurenine system. Recent studies identified conflicting associations between altered levels of TRYCATs and genetic polymorphisms in major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD).

The Postpartum Obsessive-Compulsive Scale: Psychometric, Operative and Epidemiologic Study in a Portuguese Sample.

Background: Although obsessive-compulsive (OC) symptoms are common in the perinatal period, measures to comprehensively assess their presence, frequency, interference and severity are lacking. The Perinatal Obsessive-Compulsive Scale (POCS) is the only self-report questionnaire with context-specific items. It includes items to assess perinatal-specific obsessions and compulsions, a severity scale and an interference scale.

Extent to which array genotyping and imputation with large reference panels approximate deep whole-genome sequencing.

Understanding the genetic basis of human diseases and traits is dependent on the identification and accurate genotyping of genetic variants. Deep whole-genome sequencing (WGS), the gold standard technology for SNP and indel identification and genotyping, remains very expensive for most large studies. Here, we quantify the extent to which array genotyping followed by genotype imputation can approximate WGS in studies of individuals of African, Hispanic/Latino, and European ancestry in the US and of Finnish ancestry in Finland (a population isolate).

What Have We Learned About the Genetics of Obsessive-Compulsive and Related Disorders in Recent Years?

Obsessive-compulsive disorder (OCD) is a complex, multifactorial disorder with onset in either childhood or early adulthood. Lifetime prevalence has been estimated to be around 2%-3%. groups OCD together with closely related disorders-body dysmorphic disorder, trichotillomania (hair-pulling disorder), hoarding disorder, and excoriation disorder (skin-picking disorder)-as obsessive-compulsive and related disorders (OCRDs).

Whole-genome analysis of human embryonic stem cells enables rational line selection based on genetic variation.

Despite their widespread use in research, there has not yet been a systematic genomic analysis of human embryonic stem cell (hESC) lines at a single-nucleotide resolution. We therefore performed whole-genome sequencing (WGS) of 143 hESC lines and annotated their single-nucleotide and structural genetic variants. We found that while a substantial fraction of hESC lines contained large deleterious structural variants, finer-scale structural and single-nucleotide variants (SNVs) that are ascertainable only through WGS analyses were present in hESC genomes and human blood-derived genomes at similar frequencies.