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Study Finds GADL1 SNPs Highly Predictive of Bipolar Lithium Response in Han Chinese

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A study by researchers from Taiwan’s Academia Sinica has identified a set of SNPs in the GADL1 gene that are highly predictive of Han Chinese bipolar patients’ response to lithium therapy.

The group published the finding in a report in the New England Journal of Medicine last month.

Yuan-Tsong Chen, one of the study’s authors, told Pharmacogenomics Reporter in an email this week that the strongly predictive nature of the SNPs the group identified was not a “total surprise.”

“We have been studying pharmacogenomics of inter-individual differences in drug responses, such as efficacy, dose requirements, and adverse events for many years. We believe individual difference in drug response has a larger genetic component than individual difference in susceptibility for common diseases,” he explained.

“I think our success of finding a variant strongly associated with lithium response [was based on using] a stringent phenotype criteria, and our population [being] genetically more homogenous,” Chen added.

In the study, the researchers collected genotype data from a discovery cohort of 294 Chinese patients with bipolar disorder who had received lithium treatment with good adherence for at least two years to identify potential genetic regions associated with a response to the drug.

These patients were selected out of a larger GWAS study of 1,647 patients with bipolar disorder recruited from 25 psychiatric departments and institutions participating in an effort called the Taiwan Bipolar Consortium.

To establish a firm set of phenotype data with which to conduct the study, the team carefully evaluated this cohorts’ disease course based on direct interviews with patients and their family members, interviews with in-charge psychiatrists, as well as medical-chart review.

“Three senior psychiatrists together checked the collected data and made a reliable decision on the phenotype. The work was [laborious], but that is why we were able to get this finding,” Andrew Cheng, the study’s senior corresponding author told PGx Reporter in an email.

Using a scoring tool called the Alda scale — which takes into account a patient’s reduction in illness activity and compares the frequency, duration, and severity of episodes during lithium treatment with the frequency, duration, and severity of episodes during periods in which the patient was not receiving lithium — the team recorded a lithium response phenotype for each subject.

The group then searched for genetic variants associated with lithium response using four different Alda scale cutoff points.

GWAS data for those patients within this larger study who had been treated with lithium with good adherence to therapy revealed that SNPs on chromosome 3p24.1 showed an association with a response to lithium with genomewide significance.

Two SNPs in particular, rs17026688 and rs17026651, located in the introns of the GADL1 gene, showed the strongest associations, with an Alda scale cutoff point of 5 to 6. Sensitivity and specificity for response to lithium were 93 percent and about 85 percent, respectively, for both rs17026688 and rs17026651 at this cutoff point, the authors reported.

The group then tested the association of these SNPs in two replication cohorts: one of 100 patients, and a second of 24 patients.

In the first replication cohort, the group genotyped rs17026688 and rs17026651 together with other flanking SNPs in GADL1 that had shown genomewide significance in the discovery cohort. Again, both rs17026688 and rs17026651 showed the strongest associations in this replication test, the authors wrote.

According to the report, among the 24 patients in the second replication cohort, all 16 carriers of the alleles associated with good lithium response indeed had a high Alda score — between 8 and 10 — indicating good response. All eight non-carriers, meanwhile, had a poor response with a total Alda score of only 0 to 3.

Because the SNPs that showed the strongest association were in the introns of GADL1, the researchers also looked more deeply at the gene to try to identify variants that might influence its expression. In a randomly selected group of 94 patients with good response and 94 patients with poor response to lithium from the initial discovery cohort, the group sequenced exons, intron-exon boundaries, and a promoter region.

This revealed a functional splice variant, which, when genotyped in the full 418 patients evaluated in the study, was shown to be in complete linkage disequilibrium with rs17026688.

According to the authors, the study suggests that these three variants — rs17026651, GADL1 IVS8+48delG, and rs17026688 — could all be potentially clinically useful biomarkers to predict response to lithium therapy in bipolar patients of Asian ancestry.

Cheng said in his email to PGx Reporter that there have been earlier genome-wide association studies of response to lithium to prevent recurrence of bipolar disorder in Caucasian populations, but no SNPs had been found to be associated with lithium response with sufficient sensitivity for clinical use.

Findings from previous studies may have been limited by their phenotype definitions of lithium response, he added. “For example, the problem of adherence to lithium may compromise the validity of classification between responder and non-responder. Another issue is combined treatment, which may confuse the attribution of response effect to one drug. Therefore, we used stringent definitions on drug response to resolve the problems in phenotype,” Cheng wrote.

Although the predictive alleles the team identified in the study are rare in persons of European and African ancestry, the authors suggested that the finding could be a hint that other GADL1 variants may influence the response to lithium therapy in such other populations.

“As pharmacogenetic results can vary with study population, we would be very interested to see if our findings apply to other populations," Chen wrote. "The GADL1 variant we reported is very rare in Caucasian and African populations, but it is still possible other variants in the GADL1 gene may influence the lithium response in other populations. We hope we can collaborate with other groups.”

Before the SNPs could potentially be used clinically to guide therapy for Han Chinese or other patients, Chen said independent confirmation by other groups and a prospective clinical trial are warranted.

He added that Academia Sinica does not have plans to try to commercialize a test based on the findings itself, but hopes that outside commercial entities might take up the project.

The authors also wrote in the paper that the potential of the identified SNPs to be predictive of drug response in affective disorders other than bipolar disorder, such as refractory major depressive disorder, could also be a promising avenue of investigation.

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