NEW YORK (GenomeWeb News) – In a sort of test case for personalized medicine, a team of clinicians and researchers used whole-genome sequencing to uncover variants possibly linked to a patient's obsessive-compulsive disorder. But, as Cold Spring Harbor Laboratory's Gholson Lyon and his colleagues reported in the journal PeerJ yesterday, knowing those variants did not change that patient's treatment for OCD.
The researchers additionally found that the patient, called by the pseudonymous initials MA, also had variants in a few genes that could influence how he metabolized certain drugs. The patient's OCD, though, was treated using deep-brain stimulation.
"On a comparative level, deep brain stimulation has thus far been a more direct and effective intervention for his mental illness than anything discovered from his whole-genome sequencing," Lyon and his colleagues wrote.
Still, the researchers said that their study underlines the power of precision medicine. "One can learn a substantial amount from detailed study of particular individuals," they added.
Some of the pharmacogenetic data, had it been available earlier in the course of the patient's treatment, likely would have affected which drugs the patient was given and at what dosage, the researchers said. They also noted that an incidental finding related to vision did affect the patient's ophthalmic care.
The patient MA, a 37-year-old man, was diagnosed with severe, treatment-refractory OCD, and he also experienced periods of depression and suicide attempts as well as paranoia. Over the course of 15 years, MA had been in a number of medication trials and took clomipramine and various SSRIs, including fluoxetine, and was treated through outpatient exposure and ritual prevention therapy.
Under a humanitarian device exception — as DBS typically is used to treat Parkinson's disease — MA underwent surgery to implant a DBS device made by Medtronic. DBS, Lyon and his colleague reported, appeared to improve MA's symptoms, noting that MA "regained a quality of life," as he was able to engage in activities that he hadn't been able to before including exercising and volunteering. The patient also began to date and eventually got married.
Meanwhile, Lyon and his colleagues delved into MA's genome, which was sequenced by Illumina in the company's CLIA-certified, CAP-accredited Clinical Services Laboratory.
While Illumina's clinical evaluation of 344 genes based on its CASAVA variant caller found no pathogenic or likely pathogenic variants, further analyses by Lyon and his colleagues based on the sequencing data and additional genotyping data using tools from Omicia Opal and AssureRx Health found a number of potentially clinically relevant variants.
For example, MA is a heterozygote for a variant in BDNF, which encodes a nerve growth factor protein that has been linked to OCD — treatment-naïve OCD patients have been found to have low BDNF serum levels. In addition, he is a heterozygote for an MTHFR allele, which has been linked to a susceptibility to psychoses, and he is a heterozygote for a catechol-O-methyltransferase gene variant, which has been linked to risk of a number of neuropsychiatric disorders in Caucasians.
"There is some evidence that MTHFR x COMT genotype interactions might also be occurring in MA to influence his neuropsychiatric status, and the same is true for BDNF x COMT interactions," Lyon and his colleagues said.
They cautioned, though, that "the data presented are not sufficient to implicate any particular mutation as being necessary or sufficient to lead to the described phenotype, particularly given that mental illness results from a complex interaction of any human with their surrounding environment and social support structures."
Lyon and his colleagues also uncovered pharmacogenomic variants within MA's genome. For example, he is heterozygous for a variant in the choline O-acetyltransferase gene that not only is linked to schizophrenia risk, but the particular allele has also been associated with increased response to olanzapine, especially in patients with schizophrenia.
Other pharmacogenetic variants indicate that MA has decreased CYP2C9 enzymatic activity and may not be able to biotransform fluoxetine, a drug to which MA showed no response.
While these pharmacogenetic findings did not affect MA's treatment, the researchers noted that they archived the results and "expect that these variants will be useful over the course of his life-long medical care."
One result, though, did lead to a change in MA's medical care, though not for his obsessive-compulsive disorder. The researchers found that MA has a variant in PHYH, which has been linked to Refsum disease, a condition characterized by vision loss as well as the loss of the sense of smell. MA, the researchers noted, was recently diagnosed with cataracts and has always had poor night vision.
"We provide our study as a cautionary one," Lyon and his colleagues said. "WGS cannot act as a diagnostic and prognostic panacea for neuropsychiatric disorders, but instead could act to elucidate risk factors for psychiatric disease and pharmacogenetic variants that can inform future medication treatments."