László Mayer

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and Childhood-Onset Mood Disorders

Background/Aims: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. Methods: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. Results: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. Conclusion: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

Association of the GABRD gene and childhood-onset mood disorders

The chromosome 1p36 region was previously indicated as a locus for susceptibility to recurrent major depressive disorder based on a linkage study in a sample of 497 sib pairs. We investigated the gamma‐aminobutyric acid A (GABAA) δ receptor subunit gene, GABRD, as a susceptibility gene to childhood‐onset mood disorders (COMD) because of substantial evidence implicating GABAergic dysfunction in mood disorders and the position of this gene near the 1p36 linkage region. Using a sample consisting of 645 Hungarian families with a child/adolescent proband diagnosed with a mood disorder with the onset of the first episode before age 15, we found some evidence for the association of two polymorphisms located within the gene, rs2376805 and rs2376803, as well as significant evidence for biased transmission of the haplotypes of these two markers (global χ2 test for haplotypes = 12.746, 3 df, P = 0.0052). Furthermore, significant evidence of association was only observed in male subjects (n = 438) when the results were analyzed by sex (χ2 = 9.000 1 df, P = 0.003 for rs2376805). This was in contrast with the previous linkage findings, as LOD scores exceeding 3 were only in female–female pairs in that study. These findings point to the GABRD gene as a susceptibility gene for COMD; however, this gene may not explain the previous linkage finding.

Stressful life events in a clinical sample of depressed children in Hungary

BACKGROUND There is limited information on the characteristics of stressful life events in depressed pediatric clinical populations and the extent to which sex, age, and their interactions may influence the relations of life events and depression. Using a very large clinical sample of children and adolescents with major depressive disorder (MDD), we therefore examined life events in various ways, as well as their relations to age and sex. METHODS The study included a clinic-based sample of 434 children (ages 7-14) with a DSM-IV diagnosis of MDD and their mothers, and a school-based comparison sample of 724 children and their mothers. Life event information was obtained from the mothers. RESULTS Children with MDD had twice the number of lifetime stressful events than did the comparison group, with very high levels of stressors by the age of 7-9 that stabilized across adolescence. In contrast, the comparison sample experienced a gradual increase in stressful life events as a function of age up to mid-adolescence. Parental health events, death of close relatives, and intrafamilial events were significantly associated with MDD diagnosis. There were significantly stronger associations between parental health- as well as death-event clusters and MDD diagnosis among younger children than adolescents. LIMITATIONS Geographical differences between the clinical and comparison samples, as well as possible parental reporting biases may affect the generalizability of these findings. CONCLUSION The association between some stressful life events and MDD seems to be moderated by age, underscoring the need to examine specific events, as well as clusters of events. Better understanding of such interactions may facilitate early identification of possible risk factors for pediatric MDD.

Age and sex analyses of somatic complaints and symptom presentation of childhood depression in a Hungarian clinical sample

OBJECTIVE To determine whether the symptom presentation of major depressive disorder (MDD) in a large clinical sample of youngsters is influenced by age, sex, and the interaction of age and sex. METHOD The sample included 559 children (mean age = 11.69 years; range, 7-14 years; 247 girls) with MDD recruited from 23 mental health facilities across Hungary. Psychiatric evaluations were conducted via the semistructured Interview Schedule for Children and Adolescents-Diagnostic Version (ISCA-D). Final DSM-IV diagnoses were rendered via the best-estimate diagnostic procedure. Evaluations were conducted between April 2000 and May 2005. RESULTS Six depression symptoms increased with age: depressed mood (odds ratio [OR] = 1.10, P < .05), hypersomnia (OR = 1.17, P < .05), psychomotor retardation (OR = 1.11 P < .05), fatigue (OR = 1.13, P < .01), thoughts of death (OR = 1.11, P < .05), and suicidal ideation (OR = 1.18, P < .01), while psychomotor agitation decreased with age (OR = 0.91, P < .05). Boys were less likely to evidence anhedonia (OR = 0.67, P < .05), insomnia (OR = 0.68, P < .05), and hypersomnia (OR = 0.56, P < .05) but more likely to have psychomotor agitation (OR = 1.59, P < .01). There were no age-by-sex interactions. Rates of somatic complaints did not decrease with age (OR = 1.01, P > .05). CONCLUSIONS The symptom presentation of MDD becomes somewhat more neurovegetative as children get older. However, girls display more affective and atypical symptoms across all age groups. Somatic complaints were common regardless of age and should be considered an associated feature of depression in children and adolescents.

G72/G30 (DAOA) and juvenile-onset mood disorders

The chromosome 13q region has been linked to bipolar disorder in a number of genome scans as well as focused linkage studies. Previously we identified linkage to the 13q32 region in a genome scan of 146 affected sibling pair families from Hungary with juvenile‐onset mood disorders. Within this region are the overlapping genes G72/G30, with G72 now officially named as D‐amino‐acid oxidase activator (DAOA). This locus has been associated with panic disorder, schizophrenia, and bipolar disorder. In this study, we tested for association to 11 markers in these genes and mood disorders in a sample of 646 nuclear families identified with a proband with onset of a mood disorder before 14.9 years of age. We identified evidence for association to three markers within the gene (rs2391191, rs3918341, rs1935062), two of which had been associated with bipolar disorder in previous studies. When corrected for the number of markers tested, the results were no longer significant, however the prior evidence for association of this gene in multiple studies points to this gene as a potential contributor to juvenile‐onset mood disorders.

Genome scan in sibling pairs with juvenile-onset mood disorders: Evidence for linkage to 13q and Xq.

Mood disorders (bipolar and depressive disorders) in children and adolescents are associated with significant morbidity and mortality. Twin and family studies, for the most part, indicate higher familiality and heritability for mood disorders that onset in childhood/adolescence than those that onset in adulthood. To identify the genetic contribution to mood disorders that onset in childhood/adolescence, we performed a genome scan on 146 nuclear families from Hungary containing an affected proband and affected siblings. In total, the pedigrees contained 303 affected children: 146 probands, 137 siblings with a first episode of mood disorder before 14.9 years of age, and 20 siblings with onset of their first episode after 14.9 years of age but before the age of 18. The results of the genome scan using 405 microsatellite markers did not provide evidence for linkage at the recommended genome wide significance level for any novel loci. However, markers on two chromosomes, 13q and Xq, provided evidence for linkage in regions previously identified as linked to bipolar disorder in multiple studies. For the marker on chromosome 13q the peak non‐parametric multipoint LOD score was at the marker D13S779 (LOD = 1.5, P = 0.004). On chromosome Xq, evidence for linkage was observed across a large region spanning two regions previously linked to bipolar disorder; Xq24 to Xq28, with a peak at marker TTTA062 (LOD 2.10, P = 0.0009) in Xq28. Results for these regions exceed the recommended P‐value for a replication study of P < 0.01 and thus provide evidence for these two loci as contributing to mood disorders with juvenile onset.

Tagging SNP Association Study of the IL-1β Gene (IL1B) and Childhood-Onset Mood Disorders

Given substantial evidence for IL‐1β involvement in the etiology of depression, the IL1B gene is a strong candidate for involvement in susceptibility to depressive disorders. However, association studies investigating this, to date, have been limited to just two polymorphisms (rs1143627[−31T/C] and rs16944[−511C/T]) that constitute only a fraction of the genetic variation that is actually present across this gene in the population. Here, in a family‐based association study of childhood‐onset mood disorders (COMD), characterized by onset of depression before the age of 15, we have used a gene‐wide approach, employing a panel of five tagging SNPs spanning the entire gene. Based on TDT analyses of both individual alleles and haplotypes, in a study sample of 646 families (with 782 affected children), none of the SNPs, including those implicated in transcriptional regulation of the gene, showed evidence for association with COMD. This is the largest and most comprehensive study of IL1B in relation to mood disorders that has been carried out, to date. The results do not support the involvement of IL1B as a major factor in genetic risk for early‐onset mood disorders.

GPR50 is not associated with childhood-onset mood disorders in a large sample of Hungarian families

We investigated the relationship of the gene for the X-linked orphan G protein-coupled receptor (GPR50) to childhood-onset mood disorders in a sample of 384 families with 468 affected children and adolescents collected in Hungary. Our choice of this gene for study was based on a previous report of an association of GPR50 with bipolar disorder and major depressive disorder. A significant association with the deletion allele of an insertion/deletion polymorphism (Δ502–505) located in exon 2 had been reported in a sample of 226 patients with major depressive disorder and 264 patients with bipolar disorder. The association was more significant in females compared with males in those samples. We used for this study a polymorphism in complete linkage disequilibrium with the Δ502–505 polymorphism, Thr532Ala (rs561077), and two additional polymorphisms, Val606Ile (rs13440581) and an intronic polymorphism (rs2072621). We found no evidence for an association for the markers analyzed individually, nor for haplotypes of these markers. Further, we found no evidence of association when the results were analyzed in girls only (n=215). We, therefore, failed to replicate the previous association of this gene with mood disorders.

Association study of N-methyl-D-aspartate glutamate receptor subunit genes and childhood-onset mood disorders

GRIN1 rs4880210 139,143,515 50 G T 0.122 0.878 76 70 0.247 0.619 rs28489906 139,158,220 Intron 2 G A 0.470 0.530 171 170 0.003 0.957 rs6293 139,171,059 Exon 6 A G 0.692 0.303 166 157 0.251 0.616 rs10747050 139,175,697 Intron 11 A G 0.951 0.049 24 33 1.427 0.232 GRIN2A rs1071504 10,187,517 50 C T 0.279 0.721 138 144 0.128 0.721 rs2302711 10,183,199 Intron 2 C T 0.282 0.718 141 140 0.004 0.952 rs1070503 10,172,675 Intron 3 C T 0.866 0.134 67 79 0.987 0.320 rs727605 9,863,065 Intron 5 G A 0.694 0.306 161 133 2.671 0.102 rs8049651 9,851,167 Exon 6 G A 0.726 0.274 153 125 2.825 0.093 rs1014531 9,763,295 Exon 14, 30UTR G A 0.617 0.383 184 163 1.272 0.260 G A 0.797 0.203 117 109 0.283 0.594 rs2284416 13,810,481 Intron 2 T G 0.464 0.536 174 189 0.620 0.431 rs2268115 13,760,992 Intron 3 T G 0.561 0.439 169 170 0.003 0.957 rs2284407 13,733,473 Intron 3 G T 0.582 0.418 186 176 0.276 0.599 rs2268097 13,644,099 Intron 9 A G 0.583 0.417 170 174 0.047 0.829 rs890 13,606,575 Exon 13, 30UTR G T 0.452 0.548 183 172 0.341 0.559

No evidence of association between a functional polymorphism in the MTHFR gene and childhood-onset mood disorders

No evidence of association between a functional polymorphism in the MTHFR gene and childhood-onset mood disorders