Autism spectrum disorder and attention deficit hyperactivity disorder have a similar burden of rare protein-truncating variants.

The exome sequences of approximately 8,000 children with autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) and 5,000 controls were analyzed, finding that individuals with ASD and individuals with ADHD had a similar burden of rare protein-truncating variants in evolutionarily constrained genes, both significantly higher than controls. This motivated a combined analysis across ASD and ADHD, identifying microtubule-associated protein 1A (MAP1A) as a new exome-wide significant gene conferring risk for childhood psychiatric disorders.

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD.

Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome.

Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay.

Bayesian refinement of association signals for 14 loci in 3 common diseases.

To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal.

Evoker: a visualization tool for genotype intensity data.

Summary: Genome-wide association studies (GWAS), which produce huge volumes of data, are now being carried out by many groups around the world, creating a need for user-friendly tools for data quality control (QC) and analysis. One critical aspect of GWAS QC is evaluating genotype cluster plots to verify sensible genotype calling in putatively associated single nucleotide polymorphisms (SNPs). Evoker is a tool for visualizing genotype cluster plots, and provides a solution to the computational and storage problems related to working with such large datasets.

Genetic profile for five common variants associated with age-related macular degeneration in densely affected families: a novel analytic approach.

About 40% of the genetic variance of age-related macular degeneration (AMD) can be explained by a common variation at five common single-nucleotide polymorphisms (SNPs). We evaluated the degree to which these known variants explain the clustering of AMD in a group of densely affected families. We sought to determine whether the actual number of risk alleles at the five variants in densely affected families matched the expected number.

Systematic haplotype analysis resolves a complex plasma plant sterol locus on the Micronesian Island of Kosrae.

Pinpointing culprit causal variants along signal peaks of genome-wide association studies (GWAS) is challenging. To overcome confounding effects of multiple independent variants at such a locus and narrow the interval for causal allele capture, we developed an approach that maps local shared haplotypes harboring a putative causal variant. We demonstrate our method in an extreme isolate founder population, the pacific Island of Kosrae.

Genome-wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae.

Background: Cardiac conduction, as assessed by electrocardiographic PR interval and QRS duration, is an important electrophysiological trait and a determinant of arrhythmia risk.

Objective: We sought to identify common genetic determinants of these measures.

Methods: We examined 1604 individuals from the island of Kosrae, Federated States of Micronesia, an isolated founder population.

Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae.

It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis.

Genome-wide association scan of attention deficit hyperactivity disorder.

Results of behavioral genetic and molecular genetic studies have converged to suggest that genes substantially contribute to the development of attention deficit/hyperactivity disorder (ADHD), a common disorder with an onset in childhood. Yet, despite numerous linkage and candidate gene studies, strongly consistent and replicable association has eluded detection. To search for ADHD susceptibility genes, we genotyped approximately 600,000 SNPs in 958 ADHD affected family trios.

Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder.

A time-to-onset analysis for family-based samples was performed on the genomewide association (GWAS) data for attention deficit hyperactivity disorder (ADHD) to determine if associations exist with the age at onset of ADHD. The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array. After data cleaning procedures, 429,981 autosomal SNPs and 930 parent-offspring trios were used found suitable for use and a family-based logrank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest.

Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.

Unlabelled: Background- Variation in LDL-cholesterol (LDL-C) among individuals is a complex genetic trait involving multiple genes and gene-environment interactions.

Methods And Results: In a genome-wide association study (GWAS) to identify genetic variants influencing LDL-C in an isolated population from Kosrae, we observed associations for SNPs in the gene encoding 3hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR). Three of these SNPs (rs7703051, rs12654264, and rs3846663) met the statistical threshold of genome-wide significance when combined with data from the Diabetes Genetics Initiative GWAS.

Integrated detection and population-genetic analysis of SNPs and copy number variation.

Dissecting the genetic basis of disease risk requires measuring all forms of genetic variation, including SNPs and copy number variants (CNVs), and is enabled by accurate maps of their locations, frequencies and population-genetic properties. We designed a hybrid genotyping array (Affymetrix SNP 6.0) to simultaneously measure 906,600 SNPs and copy number at 1.

Variation near complement factor I is associated with risk of advanced AMD.

A case-control association study for advanced age-related macular degeneration was conducted to explore several regions of interest identified by linkage. This analysis identified a single nucleotide polymorphism just 3' of complement factor I on chromosome 4 showing significant association (P<10(-7)). Sequencing was performed on coding exons in linkage disequilibrium with the detected association.

Variation in complement factor 3 is associated with risk of age-related macular degeneration.

The association of variants in complement factors H and B with age-related macular degeneration has led to more intense genetic and functional analysis of the complement pathway. We identify a nonsynonymous coding change in complement factor 3 that is strongly associated with risk of age-related macular degeneration in a large case-control sample.