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Background: Despite guidelines indicating potential clinical utility of genotyping for CYP2D6, this is not yet routinely provided. A contributing factor to this is the complexity of the locus including “structural variants” (complete or partial gene deletions and duplications). Methods: Samples with a variety of CYP2D6 genotypes according to prior data were selected from the Genome-based therapeutic drugs for depression (GENDEP) study (Huezo-Diaz et al., 2012) and subjected to TaqMan copy number variant (CNV) analysis using probes specific for different CYP2D6 regions, to the Ion S5 AmpliSeq Pharmacogenomics Panel and to PharmacoScan Solution. Translator files were written to facilitate data interpretation. Results: For samples of a CNV call of two across TaqMan or PharmacoScan CNV probes, the concordance between IonS5 and PharmacoScan was 94% (32/34), with the two nonconcordant samples having variants detected by Pharmaco- Scan that are not currently in the IonS5 panel (CYP2D6*22 and CYP2D6*25). For samples with a CNV call of one across the probes, there was 100% concordance between the two platforms. For samples with a CNV call of 3 across TaqMan or PharmacoScan CNV probes, the concordance was 94% (16/17). Concordance was less for samples with unequal call across the probes, consistent with hybrid alleles. Conclusions: The Ion S5 AmpliSeq data show a high rate of concordance with PharmacoScan solution for all types of CYP2D6 variants apart from the hybrid variants (found at 2%, 18/859 in GENDEP).

Background Antidepressant drugs are used as first-line treatment in depression, but response has been shown to be highly heterogeneous, with drugs often failing to have the desired therapeutic effect. We report on an integrative analysis from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study using gene expression from mice to inform prioritization in a human pharmacogenetic study. Methods The same two antidepressants were used in mice and humans: escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor). The animal study used four inbred strains of mice (129S1/SvlmJ, C57LB/6J, DBA/2J, and FVB/NJ). Hippocampus mRNA levels were measured in 144 animals using the Affymetrix MOE 430 v2 chip. Results Based on gene-expression analysis of strain-by-drug interactions, 17 genes differentially expressed with nortriptyline or escitalopram versus saline were prioritized in the human pharmacogenetic analysis. Single nucleotide polymorphisms tagging common sequence variation in human orthologs of these genes were tested for association with response to antidepressants in 706 participants of the GENDEP human pharmacogenetic study, treated with escitalopram or nortriptyline for 12 weeks, with available high-quality Illumina 610 quad array genotyping. Several polymorphisms in the protein phosphatase 1A gene ( PPM1A ) remained significantly associated with response to nortriptyline in humans after correction for multiple comparisons within the gene. PPM1A encodes a phosphatase involved in mitogen-activated protein kinase signaling and cell stress response. Conclusions Convergent evidence from mice and humans suggests a role of the PPM1A in response to noradrenergic but not serotonergic antidepressants.

Clinical anticipation has been reported in bipolar affective disorder (BPAD). The hypothesis that expanded trinucleotide repeats are related to anticipation and transmission pattern in families with bipolar affective disorder is tested in this study. Eighty-seven two-generation pairs of patients recruited from 29 bipolar families were analyzed. The repeat expansion detection method was used to detect CAG repeat expansions between successive generations. Significant changes in age at onset and episode frequency in successive generations were observed. Mean trinucleotide CAG repeat length between parental and offspring generation significantly increased when the phenotype increased in severity, i.e., changed from major depression, single episode or unipolar recurrent depression to BPAD. A parent-of-origin effect was also observed with a significant increase in median length CAG between G1 and G2 with maternal inheritance. This increase was observed notably in female offspring. Our findings indicate for the first time that expansion of CAG repeat length could explain the clinical observation of anticipation in families with BPAD. These results provide further support for expanded trinucleotide repeat sequences as risk factors in major affective disorders.

Linkage of bipolar (BP) illness with chromosome 18 markers located at l8p11 was recently reported. A possible role for chromosome 18 in the etiology of BP illness was implicated previously by the finding in three unrelated patients of a ring chromosome with breakpoints and deleted segments at 18pter-p11 and 18q23-qter. To test the potential importance of a gene defect on chromosome 18 in our material, we examined linkage with chromosome 18 markers in two families with multiple patients with BP illness or BP spectrum disorders. Fourteen simple tandem repeat polymorphisms were used located in the chromosomal region 18p11 to 18q23 and separated by distances of approximately 10 cM on the genetic map. In one family linkage to chromosome 18 could not be excluded. Linkage and segregation analysis in the family suggests that the 12-cM region between D18S51 and D18S61 located at 18q21.33-q23 may contain a candidate gene for BP illness.

Searching for genetic risk factors of major affective disorders, segregation and association methodologies are being applied to these complex diseases which will hopefully lead to a better understanding of their genetic etiology. Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, has been considered a candidate gene in bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD). Indeed, a dysfunction of the catecholaminergic system is likely to be implicated in the pathogenesis of affective disorders (Schatzberg and Schildkraut 1995 for review). The TH gene is located on the short arm of chromosome 11 (1 lp15) and has been the subject of numerous linkage and association studies in BPAD. Linkage with TH was tested in different set of BPAD families. Most reports significantly excluded linkage between the TH gene and BPAD (Pauls et al 1991; Mendlewicz et al 1991; Mitchell et al 1991; Coon et al 1993; De bruyn et al 1994; Detera-Wadleigh et al 1994; Ewald et al 1994), however, in some families linkage