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WCPG 2015—Awards, Epigenetics, and Exomes

29 Oct 2015

On Sunday morning, October 18, at the World Congress on Psychiatric Genetics in Toronto, Canada, the Theodore Reich Young Investigator award was presented to Sarah Medland of the Queensland Institute of Medical Research in Brisbane, Australia. Medland chairs the genetics team of ENIGMA, a six-year-old imaging genetics consortium of over 500 scientists in 35 countries. Medland highlighted recent ENIGMA findings, including the detection of common variants associated with hippocampal volume in a combined sample of 22 cohorts (see SRF related news report), and common alleles associated with subcortical volumes ( van Erp et al., 2015). So far, no overlaps have emerged between SNPs associated with subcortical brain volumes and those associated with schizophrenia by the Psychiatric Genomic Consortium's (PGC) genomewide association study (GWAS) for schizophrenia. Medland suggested such overlaps may well emerge for hippocampal volume, or cortical volumes, which ENIGMA is now analyzing.

The Snow and Ming Tsuang Lifetime Achievement Award went to Michael Owen of Cardiff University in Wales. In his talk, Owen described the recent history of schizophrenia genetics, calling 2008 the field's "annus mirabilis," as it was then that systematic screening for copy number variants (CNVs) revealed that these rare deletions and duplications of DNA segments contributed to schizophrenia risk. Then followed the PGC's GWAS, which he called "an achievement of brute force and collectivism." These two types of genetic risk, however, do not mean that there are two types of schizophrenia, Owen said, pointing to their recent study suggesting that they work together (see SRF related news report).

Knowing what the genetic clues mean for biology is a greater challenge, but Owen seemed heartened by a convergence on synapse-related molecules. He ended his talk with a plea to collect very large and well-phenotyped samples, given that genetic signals are crossing diagnostic boundaries. He also noted the need to address the "annotation gap" that leaves researchers unsure about the function of much of the genome, including places harboring risk variants for schizophrenia. Finally, he urged people to remember the possibility of protective alleles, which his recent work has revealed (SRF related news report).

In an afternoon plenary talk, Art Petronis of the University of Toronto gave a primer on epigenetic mechanisms afoot in the genome. Epigenetics refers to the chemical modifications made to DNA or nearby histones that control gene expression. Petronis likened epigenetics to traffic signals, governing the comings and goings of the genome's products. As such, some researchers have looked toward epigenetics to explain features of psychiatric diseases, including discordance among identical twins, and age of onset. Petronis provided evidence that whether a site is methylated or not may be determined by the underlying DNA itself in schizophrenia, with allele-specific methylation marks enriched in functional parts of the genome, such as promoters or enhancers.

In a later session that afternoon, Viviane Labrie of Petronis' lab demonstrated how epigenetic modifications could help explain the delayed onset of complex diseases, including schizophrenia, using lactose intolerance as a model. The gene encoding lactase (LCT), needed to digest lactose, is gradually turned off in people with a certain DNA haplotype; Labrie showed that this haplotype was associated with epigenetic modifications targeted at the regulatory elements controlling LCT expression, which accrue over time. This suggests that epigenetics may determine the timing of when a risk allele has an impact.

In the same session, Tarjinder Singh of the Wellcome Trust Sanger Institute gave a glimpse into his group's exome sequencing efforts on the UK10K project. Combining their exome data with a Swedish sample to give over 4,200 schizophrenia cases and 9,000 controls, the researchers found no rare coding mutations that hit the same gene enough times to implicate it with statistical confidence, similar to the results of smaller exome sequencing studies (see SRF related news report). Combining these data with a previously published de novo dataset, however, and narrowing in on the most damaging, loss-of-function mutations, did produce a gene-specific result for KMT2F (also known as SET1DA), which encodes an enzyme that marks genes for transcription with methyl groups; the same gene has been fingered previously (see SRF related news report). The risk conferred by KMT2F loss-of-function mutations vied with that of 22q11.2 deletions, schizophrenia's most potent risk factors, and similar mutations turned up in other datasets, including a cohort with developmental delay, with carriers sharing some amount of cognitive impairment, if not schizophrenia.—Michele Solis.