‘Missing’ schizophrenia heritability found
medwireNews: Researchers have matched up single nucleotide polymorphism (SNP) sets with clinical syndromes to show that previously identified genetic variants can account for nearly all cases of schizophrenia.
The combined individual effects of 2891 SNPs previously associated with schizophrenia accounted for just 24% of the liability to schizophrenia in the cohort – 4196 cases and 3827 controls in the Molecular Genetics of Schizophrenia study.
But when considered as sets, the SNPs accounted for 90% of schizophrenia cases, report Igor Zwir (Washington University School of Medicine, St Louis, USA) and team.
“Our purely data-driven analysis shows that the elusive heritability of schizophrenia is not missing, but is encoded in a complex distribution of genotypic-phenotypic relationships”, they write in The American Journal of Psychiatry.
The researchers identified SNP sets in the overall study sample, without knowledge of which individuals had schizophrenia. This produced 723 sets; individuals and SNPs could appear in more than one set.
In all, carriers of 98 of these sets had a more than 66% risk of having schizophrenia, with carriers of 42 of the sets having at least a 70% risk. Carriers of one set had a 100% risk; in other words, all nine carriers of the nine SNPs in that set had schizophrenia. This was the smallest set, in terms of patients, to be associated with schizophrenia, with others containing between 22 and 877 individuals and between three and 32 SNPs.
The team was able to divide the sets with at least a 70% schizophrenia risk into 17 genotypic networks with no overlap between either SNPs or patients, “suggesting that these are distinct antecedents of schizophrenia.”
The SNPs in these networks were associated with genes involved in pathways such as neural development, neurotrophin function and neurotransmission. Gene products common to these pathways have previously been linked to schizophrenia risk or found to be abnormally expressed in the brains of schizophrenia patients.
“The emerging picture is suggestive of a possible pathophysiology in which abnormal brain development interacts with environmental events triggering abnormal or exaggerated immune and oxidative processes that increase risk of schizophrenia”, says the team.
The researchers then matched up the SNP sets to patients’ symptoms, by creating 342 sets of clinical features without reference to patients’ genetics. The phenotypic sets were significantly associated with the SNP sets, although the associations were complex. However, the team successfully grouped the associations into eight classes of schizophrenia, distinguished by positive and negative/disorganised symptoms and the severity of the disease course.
They also replicated their findings in the independent CATIE and Portuguese Island cohorts.
“[O]ur results hold promise for the emergence of a new era in clinical psychiatry in which person-centered treatment of complex disorders can be guided by reliable assessments of well-validated clinical syndromes and their specific causes”, the researchers conclude.
medwireNews (www.medwirenews.com) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2014
By Eleanor McDermid, Senior medwireNews Reporter