Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.

In studies of individuals of primarily European genetic ancestry, common and low- frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole genome sequencing (∼27X) of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study).

A multi-ancestry genetic reference for the Quebec population.

While international efforts have characterized genetic variation in millions of individuals, the interplay of environmental, social, cultural, and genetic factors is poorly understood for most worldwide populations. The province of Quebec in Canada has been the site of numerous genetic studies, often focusing on individual Mendelian diseases in founder sub-populations. Here, we profiled and analyzed genome-wide genotyped variation in 29,337 Quebec residents from the large population-based cohort CARTaGENE (CaG), including rich phenotype and environmental data.

Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤ 50 IU/dL) in the general population is underexplored.

Objectives: To identify genetic variants influencing VWF:Ag levels ≤ 50 IU/dL.

Disentangling the effects of sex and gender on ɛ4-related neurocognitive impairment.

Introduction: The apolipoprotein E () ɛ4 allele is a well-established risk factor for neurocognitive impairment (NCI), with varying impacts between men and women. This study investigates the distinct roles of sex and gender in modifying ɛ4-related NCI.

Methods: Biological sex was inferred from sex chromosomes, and a femininity score (FS) was used as a proxy for gender.

Astrocytic RNA editing regulates the host immune response to alpha-synuclein.

RNA editing is a posttranscriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte-specific, ADAR1-mediated RNA editing in neuroinflammation in Parkinson's disease (PD). We generated human induced pluripotent stem cell-derived astrocytes, neurons and cocultures and exposed them to small soluble alpha-synuclein aggregates.

The relationship between kidney health and neurodegenerative diseases.

Neurodegenerative diseases are multi-faceted disorders influenced by and affecting more than just the brain and nervous system. Here, we provide a review of the potential links, including mechanistic and genetic, between kidney health and neurodegeneration, mainly dementia and the two most prevalent late-onset neurodegenerative disorders, Alzheimer's disease and Parkinson's disease. We also discuss lines of evidence from various study designs and methodologies that either support or do not support an association between kidney health and neurodegeneration.

Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits.

Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.

In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole genome sequencing of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study).

Association of Genetically Predicted Skipping of COL4A4 Exon 27 with Hematuria and Albuminuria.

Key Points: Using transcriptome-wide association studies, we identified an association between splicing out of exon 27 of COL4A4 and hematuria. We confirmed the presence of COL4A4 exon 27 splicing in an independent cohort. Functional assays revealed that the COL4A4 transcript with exon 27 spliced out affects collagen IV trimer assembly and secretion.

Systematic Review and Phenome-Wide Scans of Genetic Associations with Vascular Cognitive Impairment.

Vascular cognitive impairment (VCI) is a heterogenous form of cognitive impairment that results from cerebrovascular disease. It is a result of both genetic and non-genetic factors. Although much research has been conducted on the genetic contributors to other forms of cognitive impairment (e.

Leveraging sex-genetic interactions to understand brain disorders: recent advances and current gaps.

It is established that there are sex differences in terms of prevalence, age of onset, clinical manifestations, and response to treatment for a variety of brain disorders, including neurodevelopmental, psychiatric, and neurodegenerative disorders. Cohorts of increasing sample sizes with diverse data types collected, including genetic, transcriptomic and/or phenotypic data, are providing the building blocks to permit analytical designs to test for sex-biased genetic variant-trait associations, and for sex-biased transcriptional regulation. Such molecular assessments can contribute to our understanding of the manifested phenotypic differences between the sexes for brain disorders, offering the future possibility of delivering personalized therapy for females and males.

GWAS for the composite traits of hematuria and albuminuria.

Our GWAS of hematuria in the UK Biobank identified 6 loci, some of which overlap with loci for albuminuria suggesting pleiotropy. Since clinical syndromes are often defined by combinations of traits, generating a combined phenotype can improve power to detect loci influencing multiple characteristics. Thus the composite trait of hematuria and albuminuria was chosen to enrich for glomerular pathologies.

Genetically predicted waist-to-hip circumference ratio and coronary artery disease: A sex-specific Mendelian randomization study.

Coronary artery disease (CAD) affects millions of individuals worldwide and results in a substantial burden to healthcare systems. Although it is established that CAD affects females differently than males, differences between the sexes are not routinely accounted for. Body mass index is a known risk factor for CAD.

Regional genetic correlations highlight relationships between neurodegenerative disease loci and the immune system.

Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are devastating complex diseases resulting in physical and psychological burdens on patients and their families. There have been important efforts to understand their genetic basis leading to the identification of disease risk-associated loci involved in several molecular mechanisms, including immune-related pathways. Regional, in contrast to genome-wide, genetic correlations between pairs of immune and neurodegenerative traits have not been comprehensively explored, but could uncover additional immune-mediated risk-associated loci.

Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases.

Genetic correlation ([Formula: see text]) between traits can offer valuable insight into underlying shared biological mechanisms. Neurodegenerative diseases overlap neuropathologically and often manifest comorbid neuropsychiatric symptoms. However, global [Formula: see text] analyses show minimal [Formula: see text] among neurodegenerative and neuropsychiatric diseases.

Evaluation of polygenic risk scores to differentiate between type 1 and type 2 diabetes.

Polygenic risk scores (PRS) quantify the genetic liability to disease and are calculated using an individual's genotype profile and disease-specific genome-wide association study (GWAS) summary statistics. Type 1 (T1D) and type 2 (T2D) diabetes both are determined in part by genetic loci. Correctly differentiating between types of diabetes is crucial for accurate diagnosis and treatment.

A fast linkage method for population GWAS cohorts with related individuals.

Linkage analysis, a class of methods for detecting co-segregation of genomic segments and traits in families, was used to map disease-causing genes for decades before genotyping arrays and dense SNP genotyping enabled genome-wide association studies in population samples. Population samples often contain related individuals, but the segregation of alleles within families is rarely used because traditional linkage methods are computationally inefficient for larger datasets. Here, we describe Population Linkage, a novel application of Haseman-Elston regression as a method of moments estimator of variance components and their standard errors.