Columbia University researchers have identified four potentially key genes that may play significant roles in the development of schizophrenia, and potentially hundreds of other risk-related mutations. In what they claim is the largest and most comprehensive study of its kind, the investigators sequenced the exomes of 231 schizophrenia patients and both parents (proband-parent trios) to hunt for spontaneous mutations linked with the disease. The families were recruited from U.S. and Afrikaner populations with very different demographic structures and histories.

The results identified numerous de novo nonsynonymous single nucleotide variants, as well as gene-disruptive de novo mutations in the patients, but not their parents, including repeated spontaneous disruptions in four genes (LAMA2, DPYD, TRRAP, and VPS39) within both populations that weren’t mutated in any of the control individuals. Overall, data from the Afrikaner cohort indicated that at least 17.6% of sporadic schizophrenia cases carried a de novo pathogenic exonic mutation, and at least 9.9% carried a de novo CNV. “Thus, such mutations may contribute to risk in approximately one-fourth to one-third of all sporadic cases,” state Maria Karayiorgou, M.D. and colleagues.

One of the most notable findings was that a significant proportion of the mutated genes are highly expressed in early fetal life, and these mutations were enriched among adult cases who had displayed early prepsychotic deviant behaviors. “Our findings provide a mechanistic context to interpret epidemiological correlations among various prenatal environmental insults during the first and second trimesters of pregnancy and risk for schizophrenia,” the team writes in their published paper in Nature Genetics. “Moreover, the fact that expression of many prenatally biased genes is under strict miRNA control may explain emerging links between miRNA dysregulation and psychiatric disorders. The challenge remains to identify the affected biological processes and neural circuits and to determine how they are affected.”

The researchers in fact estimate that there are more than 850 schizophrenia risk loci. “The chance that two patients have exactly the same mutation or combination of mutations is rather small,” notes Dr. Karayiorgou. “What is intriguing is that despite this variability, people with schizophrenia tend to have, more or less, the same phenotype—that is, the same clinical presentation. Our hypothesis is that many neural circuits are extremely important in schizophrenia and that these circuits are vulnerable to a number of influences. So, when any of the genes involved in these circuits are mutated, the end result is the same.”

The Columbia University Medical Center researchers and collaborators describe their findings in a paper titled “De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia”.

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