A latent genetic subtype of major depression identified by whole-exome genotyping data in a Mexican-American cohort.

Identifying data-driven subtypes of major depressive disorder (MDD) is an important topic of psychiatric research. Currently, MDD subtypes are based on clinically defined depression symptom patterns. Although a few data-driven attempts have been made to identify more homogenous subgroups within MDD, other studies have not focused on using human genetic data for MDD subtyping. Here we used a computational strategy to identify MDD subtypes based on single-nucleotide polymorphism genotyping data from MDD cases and controls using Hamming distance and cluster analysis. We examined a cohort of Mexican-American participants from Los Angeles, including MDD patients (n=203) and healthy controls (n=196). The results in cluster trees indicate that a significant latent subtype exists in the Mexican-American MDD group. The individuals in this hidden subtype have increased common genetic substrates related to major depression and they also have more anxiety and less middle insomnia, depersonalization and derealisation, and paranoid symptoms. Advances in this line of research to validate this strategy in other patient groups of different ethnicities will have the potential to eventually be translated to clinical practice, with the tantalising possibility that in the future it may be possible to refine MDD diagnosis based on genetic data.

Influence of admixture components on CYP2C9*2 allele frequency in eight indigenous populations from Northwest Mexico.

We previously documented the lowest frequency of CYP2C9*2 in Mexican indigenous Tepehuanos followed by Mestizos and Mexican-Americans populations, suggesting a negative correlation between the CYP2C9*2 frequency and the degree of Asian ancestry in indigenous Americans. We determined the influence of ethnic admixture components on the CYP2C9 allele distribution in 505 Amerindian from eight indigenous populations through genotyping CYP2C9*2, *3 and *6 alleles by real-time PCR and molecular evaluation of ancestry. The frequencies for CYP2C9*2 were 0.026 in Seris and 0.057 in Mayos, being higher than in Asians (P<0.001). CYP2C9*3 was found in Tarahumaras (0.104), Mayos (0.091), Tepehuanos (0.075), Guarijíos (0.067), Huicholes (0.033) and Coras (0.037), with East Asians having lower frequencies than the former three groups (P<0.001). CYP2C9*6 was not found. The frequency of CYP2C9*2 was lower in Amerindians than in European populations, and higher than their Asian ancestors. The presence of this allele in ethnic groups in Mexico can be explained by European admixture.

CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards.

Earlier we had found that the CYP2C9*2 allelic frequency was lower in Mexican-Americans living in California than in Spaniards (SP). This was assumed to be related to the low CYP2C9*2 and *3 allele frequencies in Orientals. This study was therefore aimed at analyzing whether there were also differences in CYP2C9 allele frequencies between Mexican-Tepehuanos (MT) and Mexican-Mestizos (MM) living in northwestern Mexico and SP. The CYP2C9*2 frequency was expected to be lower in the indigenous MT than in the two other groups, and lower in MM than in SP as in our earlier study. CYP2C9 genotypes and allele frequencies of two populations of healthy volunteers, MT (n=99) and MM (n=102), were compared with a population of SP (n=327). The data were also compared with our previously published population of Mestizo-Mexican-Americans (MA). The CYP2C9 genotypes among the studied populations were in equilibrium. The frequencies of CYP2C9*2 were 0.01, 0.07, 0.08, and 0.16 for MT, MM, MA, and SP subjects, respectively. In agreement with our hypothesis, CYP2C9*2 was significantly lower in the Mexican populations than in the SP (P<0.05), and among Mexicans in the MT than in the MM and MA groups (P<0.05), which presented similar frequencies. Moreover, the frequency of CYP2C9*3 was found to be lower (P<0.05) in MM (0.015) and MT (0.015) than in MA (0.06) and SP (0.08). Finally, the CYP2C9*6 allele was present just in one MM subject, and CYP2C9*4 and *5 were not found in the studied populations. Therefore, these findings add further evidence about CYP2C9 genetic diversity within Hispanic populations with regard to their ancestry. Considering that CYP2C9*2 and CYP2C9*3 alleles have altered catalytic activities relative to CYP2C9*1, the present data suggest the need for pharmacogenetic studies to optimize drug dosages in different populations.

Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans.

We studied seven genes that reflect events relevant to antidepressant action at four sequential levels: (1) entry into the brain, (2) binding to monoaminergic transporters, and (3) distal effects at the transcription level, resulting in (4) changes in neurotrophin and neuropeptide receptors. Those genes are ATP-binding cassette subfamily B member 1 (ABCB1), the noradrenaline, dopamine, and serotonin transporters (SLC6A2, SLC6A3 and SLC6A4), cyclic AMP-responsive element binding protein 1 (CREB1), corticotropin-releasing hormone receptor 1 (CRHR1) and neurotrophic tyrosine kinase type 2 receptor (NTRK2). Sequence variability for those genes was obtained in exonic and flanking regions. A total of 56 280 000 bp across were sequenced in 536 unrelated Mexican Americans from Los Angeles (264 controls and 272 major depressive disorder (MDD)). We detected in those individuals 419 single nucleotide polymorphisms (SNPs); the nucleotide diversity was 0.00054 + or - 0.0001. Of those, a total of 204 novel SNPs were identified, corresponding to 49% of all previously reported SNPs in those genes: 72 were in untranslated regions, 19 were in coding sequences of which 7 were non-synonymous, 86 were intronic and 27 were in upstream/downstream regions. Several SNPs or haplotypes in ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1 and NTRK2 were associated with MDD, and in ABCB1, SLC6A2 and NTRK2 with antidepressant response. After controlling for age, gender and baseline 21-item Hamilton Depression Rating Scale (HAM-D21) score, as well as correcting for multiple testing, the relative reduction of HAM-D21 score remained significantly associated with two NTRK2-coding SNPs (rs2289657 and rs56142442) and the haplotype CAG at rs2289658 (splice site), rs2289657 and rs2289656. Further studies in larger independent samples will be needed to confirm these associations. Our data indicate that extensive assessment of sequence variability may contribute to increase understanding of disease susceptibility and drug response. Moreover, these results highlight the importance of direct re-sequencing of key candidate genes in ethnic minority groups in order to discover novel genetic variants that cannot be simply inferred from existing databases.

Global meta-analysis of the C-11377G alteration in the ADIPOQ gene indicates the presence of population-specific effects: challenge for global health initiatives.

Type II diabetes mellitus is currently globally one of the fastest growing non-communicable diseases, especially in developing countries. This investigation reports on a meta-analysis undertaken of the C-11377G locus within the adiponectin gene in a black South African, a Cuban Hispanic and a German Caucasian cohort. Genotyping was performed via a real-time PCR strategy. Both fixed- and random-effects models were tested to describe the diabetes risk at both the cohort and population levels. The 2,2 genotype may only be associated with increased diabetes risk in the Cuban Hispanic cohort. Population-specific effects may have masked these associations upon meta-analytical analysis, as no significant odds ratio could be determined. Thus, to examine diabetes risk, a more global approach including the design of population-specific experimental strategies should be used, which will be crucial in developing health education and policies in a global health programme.

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans.

There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n=54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.1+/-4.5 vs 37.1+/-6.9%, respectively, P=0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.3+/-4.3 vs 51.2+/-6.0%, respectively, P=0.03). In those with lower-anxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb.org.

Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards.

Interethnic differences in cytochrome P450 polymorphism might be responsible, at least in part, for the variations in drug disposition between ethnic groups. Of the various CYP2C9 alleles, CYP2C9*2 and CYP2C9*3 have been reported to have altered catalytic activities compared to the wild-type CYP2C9*1. The present study is aimed at analysing the CYP2C9 polymorphism in a Mexican-American compared with a Spanish population. Differences between the two populations of healthy volunteers, Mexican-Americans (n=98 subjects) and Spaniards (n=102 subjects), regarding the CYP2C9 allele frequencies have been found. CYP2C9 genotypes among the studied Mexican-American population are in equilibrium. The 95% CI were, respectively, 0.81-0.90 for CYP2C9*1 (n=169), 0.05-0.13 for CYP2C9*2 (n=16) and 0.031-0.10 for CYP2C9*3 (n=11). CYP2C9*4, *5 and *6 were found in none of the studied subjects. The frequency of CYP2C9*2 was lower among Mexican-Americans compared to Spaniards (P<0.05). The obtained frequency of CYP2C9 alleles is compatible with the genomic assembly of the constitutive potential ethnic origin of this population, and supports the need of pharmacogenetic studies for optimizing the recommended drug dosages to Mexican-Americans.

The neuroimmune-endocrine axis: pathophysiological implications for the central nervous system cytokines and hypothalamus-pituitary-adrenal hormone dynamics

Cytokines are molecules that were initially discovered in the immune system as mediators of communication between various types of immune cells. However, it soon became evident that cytokines exert profound effects on key functions of the central nervous system, such as food intake, fever, neuroendocrine regulation, long-term potentiation, and behavior. In the 80's and 90's our group and others discovered that the genes encoding various cytokines and their receptors are expressed in vascular, glial, and neuronal structures of the adult brain. Most cytokines act through cell surface receptors that have one transmembrane domain and which transduce a signal through the JAK/STAT pathway. Of particular physiological and pathophysiological relevance is the fact that cytokines are potent regulators of hypothalamic neuropeptidergic systems that maintain neuroendocrine homeostasis and which regulate the body's response to stress. The mechanisms by which cytokine signaling affects the function of stress-related neuroendocrine systems are reviewed in this article.

The neuroimmune-endocrine axis: pathophysiological implications for the central nervous system cytokines and hypothalamus-pituitary-adrenal hormone dynamics.

Cytokines are molecules that were initially discovered in the immune system as mediators of communication between various types of immune cells. However, it soon became evident that cytokines exert profound effects on key functions of the central nervous system, such as food intake, fever, neuroendocrine regulation, long-term potentiation, and behavior. In the 80's and 90's our group and others discovered that the genes encoding various cytokines and their receptors are expressed in vascular, glial, and neuronal structures of the adult brain. Most cytokines act through cell surface receptors that have one transmembrane domain and which transduce a signal through the JAK/STAT pathway. Of particular physiological and pathophysiological relevance is the fact that cytokines are potent regulators of hypothalamic neuropeptidergic systems that maintain neuroendocrine homeostasis and which regulate the body's response to stress. The mechanisms by which cytokine signaling affects the function of stress-related neuroendocrine systems are reviewed in this article.