Darya Gaysina

No Association With the 5,10-Methylenetetrahydrofolate Reductase Gene and Major Depressive Disorder : Results of the Depression Case Control (DeCC) Study and a Meta-Analysis

Unipolar major depressive disorder (MDD) is a complex disorder thought to result from multiple genes in combination with environmental and developmental components. The 5,10‐methylenetetrahydrofolate reductase gene (MTHFR) has been implicated in MDD in a meta‐analysis of association studies and is within a linkage region suggested by a recent study of affected sib pairs. A single base mutation in the MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme. The MTHFR 677TT genotype, and to a lesser extent the 677CT genotype, is associated with a significant elevation in the circulating concentrations of homocysteine and a decrease in serum folate concentrations. This may parallel a similar reduction in 5‐methyltetrahydrofolate in the CNS, leading to a potential reduction in monoamine neurotransmitter function and an elevated risk of depressive disorder. To test the hypothesis that the MTHFR C677T polymorphism is involved in the predisposition to MDD, we conducted an association study of 1,222 patients with recurrent MDD and 835 control subjects. This allows 99% power to detect an effect of the size reported in the study of Bjelland et al. 2003 , however no significant differences in genotype or allele frequencies between depressive patients and controls were observed. This was the case in the sample as a whole, and when females and males were considered separately. Our findings suggest that the MTHFR C677T polymorphism is not involved in the etiology of clinically significant recurrent MDD.

Ethnic differences in the serotonin transporter polymorphism (5-HTTLPR) in several European populations

The serotonin transporter (5-HTT) is a protein that has a major role in divergent psychiatric disorders, personality traits and behaviors, by regulating serotonergic synaptic function. Transcriptional activity of the 5-HTT gene (5-HTT or SLC6A4) is modulated by a polymorphic repetitive element (5-HTT gene-linked polymorphic region, 5-HTTLPR), which consists of a 44-base pairs insertion-deletion in the promoter region, creating a short (S) allele and a long (L) allele. Ethnic differences in the allele frequencies of the 5-HTTLPR exist between Caucasian and Asian populations. This study investigated ethnic differences in 5-HTTLPR in 1804 healthy Caucasian subjects from several European populations living in Croatia and the Russian Federation. The genotype and allele frequency of the 5-HTTLPR differed significantly (P<0.001) between male and female Croats, Russians, Tatars and Bashkirs, due to the lower frequency of the S allele (38% and 37%) and S/S genotype (14% and 15%) in Croat men and women compared to other studied groups. When male and female data were collapsed, Russians had marginally different allele and genotype distribution compared to Bashkirs and Tatars. Bashkirs and Tatars had similar allele and genotype frequency. The higher frequency of the S/S genotype was found in Tatars and Bashkirs compared to Croats and Russians. Gender related differences occurred only in the allele distribution within Bashkir population. These ethnic differences might be responsible for the inconsistent findings in the studies of the association between various psychiatric disorders, personality traits, behaviors and 5-HTTLPR across different ethnicities, and should be controlled to enable the generalization of results across various population groups.

Association of the dystrobrevin binding protein 1 gene (DTNBP1) in a bipolar case-control study (BACCS).

Recent studies suggest a degree of overlap in genetic susceptibility across the traditional categories of schizophrenia and bipolar disorder. There is some evidence for an association of the dystrobrevin binding protein 1 gene (DTNBP1) with schizophrenia, and, thus, this gene has also become a focus of further investigation in bipolar disorder (BD). The aim of our study is to explore the association of DTNBP1 with BD and with a sub phenotype, presence/absence of psychotic symptoms, in a sample of 515 patients with BD (ICD10/DSMIV) and 1,316 ethnically matched control subjects recruited from the UK. Seven DTNBP1 SNPs: rs2743852 (SNP C), rs760761 (P1320), rs1011313 (P1325), rs3213207 (P1635), rs2619539 (P1655), rs16876571 and rs17470454 were investigated using the SNPlex genotyping system and 1 SNP (rs2619522) genotypes were imputed. Association analyses were conducted in a sample of 452 cases and 956 controls. We found significant differences in genotypic and allelic frequencies of rs3213207 and rs760761 of DTNBP1 between bipolar patients and controls. We also showed a global haplotypic association and an association of a particular haplotype with BD. Our results are consistent with previous studies in term of a general association between DTNBP1 and bipolar disorder and provide additional evidence that a portion of the genotypic overlap between schizophrenia and bipolar affective disorder is attributable to this gene.

The role of dopamine transporter (SLC6A3) and dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms in personality traits

Variations in personality traits are caused by interactions between multiple genes of small effect and environmental factors. To date, gender- and ethnicity-specific variations in personality have been established. In the present study, we aimed to test: (1) the effects of four polymorphisms of dopamine system genes: ANKK1/DRD2 Taq1A, DRD2 rs6275, SLC6A3 40-bp VNTR and rs27072, on personality traits; (2) whether these effects differ between men and women and between Russians and Tatars. A sample of 652 healthy individuals (222 men and 430 women) of Caucasian origin (233 Russians and 419 Tatars) from Russia was subjected to personality traits assessment with Eysenck Personality Inventory (EPI) and Temperament and Character Inventory-125 (TCI-125). The associations between each personality trait and polymorphisms were assessed with regression models adjusted for gender and ethnicity. There were significant effects of ANKK1/DRD2 Taq1A on Neuroticism (p=0.016) and of SLC6A3 rs27072 on Persistence (p=0.021) in both genders. The association between ANKK1/DRD2 Taq1A A2/A2-genotype and higher Novelty Seeking and lower Reward Dependence was shown in men only (p for gender interaction=0.018). In women only, there was a significant association between SLC6A3 10R*G-haplotype and higher Persistence (p=0.002). Our findings provide evidence for a modifying effect of gender on the associations between dopamine system genes and approach-related traits (in men) and Persistence (in women).

Symptoms of depression and anxiety, and change in body mass index from adolescence to adulthood: results from a British birth cohort

BACKGROUND Depression and anxiety have been shown to be associated with obesity and underweight, but little is known about how the relationship varies across the life course, from adolescence through adulthood. We aimed to investigate the association between adolescent- and adult-onset affective symptoms and body mass index (BMI) change from age 15 to 53 years. METHOD We used data from a British birth cohort born in 1946 and followed up ever since. The relationship between affective symptom profiles, distinguishing adolescent-onset and adult-onset symptoms, and BMI change from adolescence to age 53 years was investigated using multilevel models. RESULTS Women with adolescent-onset symptoms had lower mean BMI at age 15 years, faster rates of increase across adulthood, and higher BMI at age 53 years than those with no symptoms. Men with adolescent-onset symptoms had lower BMI at all ages from 15 to 53 years. The BMI trajectories of men and women with adult-onset symptoms did not differ from those with absence of symptoms at all ages. CONCLUSIONS The relationship between affective symptoms and change in BMI varies by sex and age at onset of symptoms. Adolescence may be an important period for the development of the association between affective symptoms and weight gain in girls. Intervention to prevent increases in BMI across adult life in women with adolescent-onset symptoms, even if they are not overweight at this age, should be considered.

The Bipolar Association case-control study (BACCS) and meta-analysis: no association with the 5,10-Methylenetetrahydrofolate reductase gene and bipolar disorder

Bipolar disorder (BD) is a complex genetic disease for which the underlying pathophysiology has yet to be fully explained. 5,10‐Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in folate‐mediated one‐carbon metabolism and folate deficiency can be associated with psychiatric symptoms. A single base variant in MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme and has recently been implicated in BD. We conducted an association study of this polymorphism in 897 patients with bipolar I or bipolar II disorder, and 1,687 healthy control subjects. We found no evidence for genotypic or allelic association in this sample. We also performed a meta‐analysis of our own, and all published data, and report no evidence for association. Our findings suggest that the MTHFR C677T polymorphism is not involved in the genetic etiology of clinically significant BD.

Association between adolescent emotional problems and metabolic syndrome: the modifying effect of C-reactive protein gene (CRP) polymorphisms

Research highlights ► Adolescent emotional problems are a risk factor for metabolic syndrome in mid life. ► CRP gene modifies the association. ► The association is stronger in CRP rs1205 CC homozygotes than in T allele carriers. ► CRP gene helps identifying depressed people at high risk for metabolic syndrome.

Adoptive Parent Hostility and Children's Peer Behavior Problems: Examining the Role of Genetically-Informed Child Attributes on Adoptive Parent Behavior

Socially disruptive behavior during peer interactions in early childhood is detrimental to childrens social, emotional, and academic development. Few studies have investigated the developmental underpinnings of childrens socially disruptive behavior using genetically sensitive research designs that allow examination of parent-on-child and child-on-parent (evocative genotype-environment correlation [rGE]) effects when examining family process and child outcome associations. Using an adoption-at-birth design, the present study controlled for passive genotype-environment correlation and directly examined evocative rGE while examining the associations between family processes and childrens peer behavior. Specifically, the present study examined the evocative effect of genetic influences underlying toddler low social motivation on mother-child and father-child hostility and the subsequent influence of parent hostility on disruptive peer behavior during the preschool period. Participants were 316 linked triads of birth mothers, adoptive parents, and adopted children. Path analysis showed that birth mother low behavioral motivation predicted toddler low social motivation, which predicted both adoptive mother-child and father-child hostility, suggesting the presence of an evocative genotype-environment association. In addition, both mother-child and father-child hostility predicted childrens later disruptive peer behavior. Results highlight the importance of considering genetically influenced child attributes on parental hostility that in turn links to later child social behavior. Implications for intervention programs focusing on early family processes and the precursors of disrupted child social development are discussed.

The catechol-O-methyltransferase gene (COMT) and cognitive function from childhood through adolescence

Highlights ► COMT gene can influence cognitive function in developmental stage specific manner. ► A large UK population-based sample with cognition measured at ages 8 and 15 years was used. ► Five functional COMT SNPs were tested for association with cognition. ► COMT rs737865 showed association with reading comprehension, verbal ability and global cognition at age 15 years in pubescent boys only. ► Further studies are necessary in order to make stronger conclusions.

Association analysis of DAOA and DAO in bipolar disorder: results from two independent case-control studies.

D-amino acid oxidase activator gene [DAOA (previously G72)] is located in a region with a positive linkage peak for bipolar disorder (BD) (13q33.2) (1). The results of case-control and family-based studies of DAOA in BD are inconsistent, with some reporting positive single marker or haplotype association (2–8) and others reporting no association (9, 10). Two meta-analyses of DAOA in BD have also provided conflicting results: one reported positive association (11), while another failed to find evidence for association (12). DAOA is an activator of DAO protein (13); both proteins are involved in the metabolism of D-serine, which plays a role in glutamatergic neurotransmission (14). Thus, there is a clear biological motivation for testing epitasis between these two genes. We explored the association of DAOA and DAO with BD and their statistical interaction in two independent case-control samples from the UK and Canada. The UK sample consisted of 515 BD patients (65% women) with a mean age (SD) of 48.0 (11.4) years. The diagnosis of BD was defined by DSMIV operational criteria using Schedules for Clinical Assessment in Neuropsychiatry (SCAN) (15). Patients with BD were classified as having a positive history of psychosis if they scored positive on at least one of the SCAN items of delusions or hallucinations (n = 232). The control sample consisted of 1,316 subjects (58% women) with a mean age (SD) of 41.7 (13.2) years, screened for lifetime absence of psychiatric disorder. The Canadian sample consisted of 385 patients (63% women) with a mean age (SD) of 46.0 (12.5) years and 312 controls (54% women) with a mean age (SD) of 43.7 (13.1) years. All enrolled subjects were of white European parentage. Both studies were approved by the local Research Ethics Committees and informed written consent was obtained from all participants. Genotyping of 10 single nucleotide polymorphisms (SNPs) was performed using SNPlex Genotyping System (Applied Biosystems, Carlsbad, CA, USA). Five DAOA SNPs: M12, M15, M18, M23, and M24, and DAO SNP were chosen on the basis of previously reported association findings. Others were chosen to get better coverage of the gene area. Overall, 9 markers cover a 95 kb region, including the 5¢ and 3¢ flanking regions of the DAOA locus, constituting the region of interest for linkage disequilibrium (LD) mapping. In total, 1,619 UK and 697 Canadian samples were genotyped. An 80% threshold was applied for the call rate across the SNP set. The call rate for each SNP varied between 94.5% and 99.7%. A total of 176 samples were regenotyped with 100% consistency. For statistical analysis, 1,408 UK and 644 Canadian samples were available. Genotype and allele frequencies were assessed for association with BD using chi-squared tests. Risk magnitudes were estimated by calculating odds ratios (OR) with 95% confidence intervals. Haplotype analysis was conducted using UNPHASED (16). Interaction analysis was performed using the Genetic Association Interaction Analysis (GAIA) application (17). We applied the Bonferroni correction for the number of genes and the number of samples investigated, and assumed that four independent tests were applied (a = 0.013). Allele frequencies of the SNPs are shown in Table 1. All genotype distributions were consistent with Hardy-Weinberg equilibrium (p > 0.05). There were no significant differences in allele or genotype frequency between cases and controls in either the UK or Canadian sample, or in the combined sample. The analysis in the subgroup with psychotic traits did not show any significant differences either (data not shown). No significant differences in global haplotype distribution or individual haplotype frequency were revealed between cases and controls in the investigated samples (Table 2). The pattern of intermarker LD of the DAOA in the two samples was similar to each other and to that in a HapMap Centre d Etude du Polymorphisme Humain (CEPH) sample (http://www.hapmap.org). Bipolar Disorders 2010: 12: 579–581 a 2010 The Authors Journal compilation a 2010 Blackwell Munksgaard