There are many genetic factors involved in causing complex illnesses such as schizophrenia. There can be chromosomal deletions, inherited or non-inherited (“de novo”) mutations in genes, as well as the effects of combinations of normal genetic variation. In addition, there is also the question of “penetrance”, or the likelihood that a particular, potentially harmful genetic variant will produce the disease in those who carry it.
In a recent study carried out by researchers from the Lieber Institute of Brain Development (LIBD), the University of Bari in Italy and the National Institute of Mental Health, the research team sought to better understand these different aspects in relation to the Neurexin 1 (NRXN1) gene, the deletion of which has previously been linked to schizophrenia. In a paper published May 2014 in Schizophrenia Research, they reported that they found that the NRXN1 deletion, though found with increased frequency in patients with schizophrenia, had “incomplete penetrance,” meaning that a number of parents and their offspring who carried the deletion did not have schizophrenia.
The study findings highlight the role of the NRXN1 deletion as a risk factor for developing schizophrenia, but not as a cause in and of itself.
Led by Richard E. Straub, Ph.D. and Daniel R. Weinberger, M.D. of LIBD, the team assembled a sample consisting of 635 people with schizophrenia, 487 of their unaffected parents, and 309 unaffected siblings, along with 635 healthy “control” subjects. Based on genotype data, they found that none of the control subjects had a deletion in the NRXN1 gene. Within the family-member samples, the deletion was seen 15 times, supporting earlier studies that showed a higher frequency of the deletion among schizophrenia patients and their first-degree relatives.
Most interestingly, though, the research team found that having the deletion did not, by itself, mean that an individual had schizophrenia. The deletion appeared in seven of the 635 patients with schizophrenia, or 1.1%, but it also appeared in five unaffected parents (1.02% of the total parent sample) and three unaffected siblings (0.97%).The NRXN1 deletion, though rare, was found almost as frequently in unaffected parents and siblings as in those who were ill.
The study findings highlight the role of the NRXN1 deletion as a risk factor for developing schizophrenia, but not as a cause in and of itself. NRXN1 deletions, the team said, “are merely risk factors that must interact with other risk factors,” including other genes as well as variables in the environment, to perturb biology in ways that give rise to clinically diagnosable illness.