18 October 2012. More than 600 people gathered in Hamburg, Germany, 14-18 October, to attend the 20th World Congress of Psychiatric Genetics, organized by Markus Nöthen of the University of Bonn, Germany, and Marcella Rietschel of the University of Heidelberg in Mannheim, Germany. Buoyed by crisp fall weather and a boisterous reception with accordions and singing the night before, participants began Monday with two plenary talks that in some ways laid out the enormity of the task of psychiatric genetics: Karl Zilles of the University of Dusseldorf, Germany, displayed the complexities of human brain organization, and Mark Daly of the Broad Institute, Cambridge, Massachusetts, described the emerging genetic architecture of psychiatric disease.
Zilles showed off detailed regional specification in the brain, as revealed by neurotransmitter receptor location, and argued that taking these subcompartments into account will be crucial to understanding their function. He ended with a meditation on connectivity, with incredible views of axon structure afforded by polarized light microscopy, which can resolve single, myelinated axons.
Daly noted that recent developments in psychiatric genetics have been propelled by technical and collaborative advances alike. An example of this is an unprecedented number of researchers from around the world, sharing their schizophrenia and control samples to the Psychiatric Genomics Consortium (PGC). This gives more power to genomewide association studies (GWAS) to detect common variants contributing to the disorder (see SRF genetics series). Indeed, Daly announced 62 new genomewide significant hits found for schizophrenia in this “second wave” of PGC GWAS, which will be presented later in the meeting. “This is truly a profound moment in schizophrenia genetics,” he said. But he also tempered any unrealistic hopes for sequencing to make everything clear. Though sequencing is revealing many, many variants, they are rare, found in cases and controls alike, and scattered across many different genes. These challenges bring to mind the growing pains of early GWAS, and Daly counseled people to stay the course with sequencing, too, as a combination of common and rare variants will contribute to genetic risk for disease.
Lousy with variants
Against that cautionary backdrop on the challenges of interpreting sequencing results, researchers gathered in a session Monday afternoon to have a look at the latest sequencing results for schizophrenia. Michael O’Donovan of Cardiff University in the U.K. began by describing the hunt for de novo mutations—spontaneously occurring, non-inherited events—in the exomes of people with schizophrenia. Stressing the preliminary nature of the findings, he reported 485 de novo events in 586 parent-child trios from Bulgaria. The rates of mutation and the number of different types of mutation were similar to those found in previous de novo exome studies in schizophrenia (see SRF related news story) and autism (see SRF related news story), but unlike these previous studies, he and his colleagues have not found more de novo events in cases compared to controls. De novo events struck 12 genes in different people, and eight genes were hit by protein-altering non-silent changes. Though these “pileups” on single genes might look suspicious, the number was not greater than expected by chance. Taking sets of genes with related function as the unit of analysis, he found that schizophrenia cases had an enrichment for de novo events in postsynaptic density gene sets highlighted last year by de novo CNVs (see SRF related news story).
Continuing the search for de novo events in the exome (see SRF related news story), Guy Rouleau of the University of Montreal, Canada, presented findings from 14 more trios from France. This turned up 15 de novo events, four of which were protein-truncating nonsense mutations. When looking at the 30 genes hit by de novo events in his work and other published de novo studies (see SRF related news story), he found that they clustered in one pathway, which did not happen for 30 randomly chosen genes. Rouleau also noted an unnerving tendency for DNA derived from lymphoblastoid cell lines to harbor de novo events not found in DNA derived from blood cells, suggesting that DNA in the cell lines can mutate on its own.
Pinning a rare variant to disease might be easier if it occurred amid less genetic background noise, such as in genetically homogeneous isolated populations—and even better if the population happens to be enriched for disease-related variants. Aarno Palotie of the Wellcome Trust Sanger Institute in Cambridgeshire, U.K., may have both in a rural Finnish isolated population with increased prevalence of schizophrenia. Using exome sequencing, he reported that eight out of 22 families so far had novel loss-of-function mutations that segregate with disease. He suggested that the number of mutations coming out of this isolate might be enough to do association statistics to test their relation to schizophrenia.
Going the case-control route, Shaun Purcell of Mount Sinai School of Medicine in New York City gave a first-pass analysis of a massive haul of variants from exome sequencing of 5,023 Swedish samples, half with schizophrenia, half controls. Of the 60,000 variants identified, 2 percent were deemed loss of function. Cases did not carry an excess of loss-of-function variants over controls, but they did show a significant enrichment for loss-of-function variants in gene sets identified by previous GWAS, copy number variations (CNV), and de novo mutation studies, including the postsynaptic density one. Purcell also described other ideas for assessing a variant’s functional relevance, one of which involved paying attention to whether the variant hits the gene in a region that encodes a domain, a working part of a protein.
Mosaic of findings
On Tuesday, Richard McCombie of Cold Spring Harbor Laboratory, New York, presented his de novo events obtained from exome sequencing of 57 schizophrenia trios. Of 59 de novo mutations, some landed in genes already implicated in autism and intellectual disability. Noting that cases had an enrichment of de novo events in five chromatin-modifying genes (e.g., CHD8), he suggested that epigenetic control of chromatin might be disrupted in schizophrenia—something that could spur mutations in a subset of cells (“somatic mosaicism”) during development (Muotri et al., 2010).
Targeting the disrupted-in-schizophrenia 1 (DISC1) gene that emerged in a Scottish family beset by mental illness (see SRF related news story), David Porteous of the University of Edinburgh, U.K., gave an update on his quest to resequence the entire DISC1 gene and the flanking TRAX1 region containing the DISC1 promoter in 240 people with schizophrenia, 221 with bipolar disorder, 192 with recurrent major depression, and 889 healthy controls. He reported 145 exome variants, but these were not overrepresented in schizophrenia or bipolar cases compared to controls. One intronic variant, however, segregated in three families with recurrent major depressive disorder.
Though exome sequencing is producing results, it is still labor intensive and expensive. Much like the SNP chips of GWAS, an exome chip containing a wide variety of variants already discovered by sequencing could give a quicker and somewhat unbiased readout of this type of variation. In a different session on Tuesday, Ben Neale of Massachusetts General Hospital in Boston presented work in progress from an Illumina exome chip that he helped design, which contains about 250,000 variants derived from 12,000 individuals. Genotyping 5,196 people with schizophrenia and 6,500 controls, however, did not turn up an overrepresentation of any one of these variants in schizophrenia.—Michele Solis.