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Schizophrenia Studies Tackle Functional Effects, Adolescent Phenotypes Linked to Risk Variants

NEW YORK (GenomeWeb) – Studies by independent research teams are refining the view of known risk variants in schizophrenia — unraveling functional insights within one strongly associated region of the genome and attempting to define early symptoms in adolescent individuals with high polygenic risk scores for the psychiatric disorder.

For the first of the papers, published online today in Nature, researchers from Harvard Medical School, the Broad Institute, and elsewhere used fine mapping to predict the functional effects of certain schizophrenia risk alleles, identifying a potential role for altered synaptic pruning in disease development.

The team focused on the major histocompatibility complex locus, a region spanning millions of bases on chromosome 6. The region showed the strongest ties to schizophrenia in a genome-wide association study that some of the same researchers published in Nature in 2014.

"These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops — something that has been greatly needed," senior author Steven McCarroll, director of genetics at the Broad Institute's Stanley Center for Psychiatric Disease, said in a statement.

McCarroll and his team scrutinized structural haplotypes — copy number patterns and expression levels — of C4 genes in the MHC locus, which code for complement component 4 proteins involved in immune response to microbes as well as synaptic pruning.

After defining haplotype diversity for the C4 isotypes C4A and C4B through droplet digital PCR analysis on 222 human chromosome 6 samples, the researchers used almost 700 post-mortem brain samples from 245 donors to try to match C4A and C4B haplotypes up with C4 gene expression profiles.

Although the expression of both C4A and C4B gene isotypes increased as gene copy number ticked up, the team noted that C4A gene expression was enhanced relative to C4B adjusting for copy number.

Using SNP data from tens of thousands of schizophrenia cases and controls, analyzed with imputation clues from the 222 chromosome 6 samples, the researchers verified ties between C4 variants and schizophrenia.

The analysis also uncovered an association involving variants between the BAK1 gene and SYNAGAP1, a gene coding for a post-synaptic density regulator.

The team's subsequent analyses supported the notion that schizophrenia association in the MHC region likely reflects effects on synapse-related genes rather than altered immunity caused by changes to MHC genes such as the human leukocyte antigen genes.

Meanwhile, in the second study, published today in JAMA Psychiatry, a University of Bristol-led team brought together genetic data for thousands of adolescent children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort who had also participated in mental health assessments.

After identifying more than 9,900 adolescent ALSPAC participants, the team narrowed in on 8,230 adolescent individuals whose SNP profiles — generated with the Illumina HumanHap550-Quad array — passed quality control steps.

That group included between 3,676 and 5,444 individuals who'd taken part in interviews aimed at assessing psychotic experiences, negative symptoms such as asocial behavior, depression, and/or anxiety when they were 12 to 18 years old.

The researchers found that adolescents expected to be at risk of schizophrenia based on variant patterns across many genes are more likely to exhibit anxiety and negative symptoms such as apathy, but did not show significantly more depressive or psychotic symptoms.

"Because the genetic risk for schizophrenia appears to be manifest as anxiety and negative symptoms during adolescence, a greater focus on these phenotypes rather than on psychotic experiences might be required for prediction of transition in at-risk samples," corresponding author Hannah Jones, a mental health researcher at the University of Bristol, and co-authors wrote.

In a related editorial in JAMA Psychiatry, Virginia Commonwealth University researcher Kenneth Kendler touched on the phenotypic findings, noting that "[w]e will surely see more studies using the [polygenic risk score] as a potentially powerful tool to clarify the phenotypic spectrum and/or developmental precursors of our major psychiatric disorders."