Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Statistical methods for clinical genome interpretation with specific application to inherited cardiac conditions

Background: While next-generation sequencing has enabled us to rapidly identify sequence variants, clinical application is limited by our ability to determine which rare variants impact disease risk. Aim: Developing computational methods to identify clinically important variants Methods and Results: (1) I built a disease-specific variant classifier for inherited cardiac conditions (ICCs), which outperforms genome-wide tools in a wide range of benchmarking. It discriminates pathogenic variants from benign variants with global accuracy improved by 4-24% over existing tools. Variants classified with >90% confidence are significantly associated with both disease status and clinical outcomes. (2) To better interpret missense variants, I examined evolutionarily equivalent residues across protein domain families, to identify positions intolerant of variations. Homologous residue constraint is a strong predictor of variant pathogenicity. It can identify a subset of de novo missense variants with comparable impact on developmental disorders as protein-truncating variants. Independent from existing approaches, it can also improve the prioritisation of disease-relevant gene for both developmental disorders and inherited hypertrophic cardiomyopathy. (3) TTN-truncating variants are known to cause dilated cardiomyopathy, but the effect of missense variants is poorly understood. Using the approach in (2), I studied the role of TTN missense variants on DCM. Our prioritised residues are enriched with known pathogenic variants, including the two known to cause DCM and others involved in skeletal myopathies. I also found a significant association between constrained variants of TTN I-set domains and DCM in a case-control burden test of Caucasian samples (OR=3.2, 95%CI=1.3-9.4). Within subsets of DCM, the association is replicated in alcoholic cardiomyopathy. (4) Finally, I also developed a tool to annotate 5’UTR variants creating or disrupting upstream open reading frames (uORF). Its utility is demonstrated to detect high-impact uORF-disturbing variants from ClinVar, gnomAD and Genomics England. Conclusion: These studies established broadly applicable methods and improved understanding of ICCs.Open Acces

Mapping Copy Number Variation by Population Scale Genome Sequencing

Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.Organismic and Evolutionary Biolog