János Réthelyi

Common variants conferring risk of schizophrenia

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Common Variants at VRK2 and TCF4 Conferring Risk of Schizophrenia

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).

Serotonin transporter promoter region (5-HTTLPR) polymorphism is associated with the intravaginal ejaculation latency time in Dutch men with lifelong premature ejaculation

INTRODUCTION Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 minute, and has been postulated as a neurobiological dysfunction with genetic vulnerability for the short IELTs, related to disturbances of central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission and 5-HT receptor functioning. AIM To investigate the relationship between 5-HT transporter gene-linked polymorphism (5-HTTLPR) and short IELTs in men with lifelong PE. METHODS A prospective study was conducted in 89 Dutch Caucasian men with lifelong PE. IELT during coitus was assessed by stopwatch over a 1-month period. Controls consisted of 92 Dutch Caucasian men. All men with LPE were genotyped for a 5-HTT-promoter polymorphism. Allele frequencies and genotypes of short (S) and long (L) variants of 5-HTTLPR polymorphism were compared between patients and controls. Association between LL, SL, and SS genotypes, and the natural logarithm of the IELT in men with LPE was investigated. MAIN OUTCOME MEASURES IELT measured by stopwatch, 5-HTTLPR polymorphism. RESULTS In men with lifelong PE, the geometric mean, median, and natural mean IELTs were 21, 26, and 32 seconds, respectively. There were no significant differences in the 5-HTT polymorphism alleles and genotypes between 89 Dutch Caucasian men with LPE (S 47%, L 53%/LL 29%, SL 48%, SS 22%) and 92 Dutch Caucasian controls (S 48%, L 52%/LL 29%, SL 45%, SS 26%). In men with lifelong PE there was a statistically significant difference between LL, SL, and SS genotypes in their geometric mean IELT (P < or = 0.027); the LL genotypes had significantly shorter IELTs than the SS and SL genotypes. CONCLUSIONS The 5-HTTLPR polymorphism is associated with significant effects on the latency to ejaculate in men with lifelong PE. Men with SS and SL genotypes have 100% and 90% longer ejaculation time, respectively than men with LL genotypes.

Expanding the range of ZNF804A variants conferring risk of psychosis

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10−8. In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR=1.08, P=0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N=609, OR=1.09, P=0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P=0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P=0.0016 for association with the larger set of psychiatric disorders).

Where psychology meets physiology: chronic stress and premature mortality: the Central-Eastern European health paradox

A substantial and still growing body of research tries to link different psychological models and chronic diseases, with special emphasis on cardiovascular disease. These efforts have established several conceptual bridges that connect psychological alterations and psychosocial factors to the risks, onset and prognosis of cardiovascular disease. However, several different models have been suggested. Depression and learned helplessness are two central psychological models that have been shown to have major explanatory power in the development of chronic diseases. In this respect the so called Central-Eastern European health paradox, that is the morbidity and mortality crisis in these transforming societies can be regarded as a special experimental model. In this review chronic stress is proposed as an integrating theory that can be applied to different psychological models. Chronic stress and allostatic load has been shown to lead to typical pathogenetic results in animal experiments. Chronic stress theory is applicable to the explanation of the suddenly changing patterns of premature mortality rates in transforming societies. Literature and the different models in the field of psychology, behavioural sciences, and epidemiology are reviewed in terms of the chronic stress theory. The applicability of these results are investigated for further research, clinical and policy implications.

Self-Rated Health, Subjective Social Status, and Middle-Aged Mortality in a Changing Society

In this study, the authors examined the relationships between self-rated health and subjective and objective socioeconomic status (as measured by income and education) in relation to middle-aged mortality differences in men and women across 20 counties in Hungary through a cross-sectional, ecological study. The authors interviewed 12,643 people in a Hungarostudy 2002 survey, profiling the Hungarian population according to gender, age, and county. They found that mean self-rated health and self-rated disability at the county level were significantly associated with middle-aged mortality differences among counties, with male mortality more closely associated with self-rated health. The authors also noted that self-rated health and socioeconomic status of the opposite gender were significantly associated with middle-aged mortality, but the strength of the association differed by gender. Finally, male middle-aged mortality was more strongly connected to female subjective and objective social status than female mortality was connected with male social status.

Comorbidity of pain-associated disability and depressive symptoms in connection with sociodemographic variables: results from a cross-sectional epidemiological survey in Hungary

&NA; The purpose of this study was to investigate the prevalence of pain symptoms causing disabilities in every‐day activities and their possible connection to depressive symptomatology. A representative sample of 12 640 adults from the Hungarian population participated in a door‐to‐door survey about demographic variables, pain‐associated disability, and depressive symptomatology. The overall prevalence of pain‐associated disability was 32.7%, significantly lower in men, showing a significant increasing trend with age. A decreasing tendency in prevalence rates was observed in connection with higher educational and occupational status. Results revealed a 30.2% prevalence of depressive symptomatology among interviewees reporting pain‐associated disabilities. The co‐prevalence of depressive symptoms revealed a significant increasing trend with age and lower educational level. No significant gender difference was found in the co‐occurrence of depressive symptoms. This survey concludes that pain symptoms constitute a substantial public health problem in the Hungarian population in forms of emerging disabilities and depression. Epidemiological studies offer a better understanding of sociodemographic differences in health status, and serve the better allocation of professional and economic resources.

Association study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample†

Genetic association studies have yielded extensive but frequently inconclusive data about genetic risk factors for schizophrenia. Clinical and genetic heterogeneity are possible factors explaining the inconsistent findings. The objective of this study was to test the association of commonly incriminated candidate genes with two clinically divergent subgroups, non‐deficit (SZ‐ND) and deficit‐schizophrenia (SZ‐D), and symptom severity, in order to test for replication of previously reported results. A homogeneous sample of 280 schizophrenia patients and 230 healthy controls of Hungarian, Caucasian descent were genotyped for polymorphisms in schizophrenia candidate genes NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A. Patients were divided into the diagnostic subgroups of SZ‐ND and SZ‐D using the Schedule for Deficit Syndrome (SDS), and assessed clinically by the Positive and Negative Symptom Scale (PANSS). SNP8NRG241930 in NRG1 and rs1011313 in DTNBP1 were associated with SZ‐ND (P = 0.04 and 0.03, respectively). Polymorphisms in RGS4, G72/G30, and PIP5K2A were neither associated with SZ‐ND nor with SZ‐D. SNP8NRG241930 showed association with the PANSS cognitive and hostility/excitability factors, rs1011313 with the negative factor and SDS total score, and rs10917670 in RGS4 was associated with the depression factor. Although these results replicate earlier findings about the genetic background of SZ‐ND and SZ‐D only partially, our data seem to confirm previously reported association of NRG1 with schizophrenia without prominent negative symptoms. It was possible to detect associations of small‐to‐medium effect size between the investigated candidate genes and symptom severity. Such studies have the potential to unravel the possible connection between genetic and clinical heterogeneity in schizophrenia.

Are patients with schizophrenia rational maximizers? Evidence from an ultimatum game study

Schizophrenia is associated with impaired social cognition and community functioning. Social decision-making strategies of healthy controls and patients with schizophrenia were compared by using the ultimatum game (UG). In this game two players have to split a sum of money. The proposer offers a portion to the responder, who decides to either accept or reject the offer. Rejection results in no income to either of the parties. Unfair proposals are frequently rejected by nonclinical individuals, a phenomenon described as altruistic punishment. Patients and controls participated in a series of UG interactions as responders in a computerized test setting. We also tested the effect of the proposers facial expression on decision-making. Our results indicate that patients with schizophrenia accepted unfair offers at a significantly higher rate than did healthy controls. In contrast, at fair proposals, the acceptance rate was lower in patients compared with controls. At higher offers, the proposers facial expression (positive/negative) significantly influenced the acceptance rate (positive facial expression increased the likelihood of acceptance) in the control group. This effect was not observed in the patient group. These results suggest that schizophrenia patients are impaired in socioeconomic interactions requiring emotion recognition and decision-making, which may result in unstable behavioral strategies.

Genes and environments in schizophrenia: The different pieces of a manifold puzzle

Genetic research targeting schizophrenia has undergone tremendous development during recent years. Supported by recently developed high-throughput genotyping technologies, both rare and common genetic variants have been identified that show consistent association with schizophrenia. These results have been replicated by independent studies and refined in meta-analyses. The genetic variation uncovered consists of common alleles, i.e. single nucleotide polymorphisms (SNPs) conveying small effects (odds ratios below 1.1) on disease risk. The source of rare variants is copy number variations (CNVs), only detectable in a small proportion of patients (3-5% for all known CNVs) with schizophrenia, furthermore extremely rare de novo mutations captured by next generation sequencing, the most recent technological advancement in the field. Despite these findings, the search for the genetic architecture underlying schizophrenia continues since these variants explain only a small proportion of the overall phenotypic variance. Gene-environment interactions provide a compelling model for resolving this paradox and interpreting the risk factors of schizophrenia. Epidemiologically proven risk factors, such as prenatal infection, obstetric complications, urbanicity, cannabis, and trauma have been demonstrated to interact with genetic risk, giving rise to higher prevalence rates or more severe symptomatology in individuals with direct or indirect genetic predisposition for schizophrenia. Further research will have to explain how the different forms of genetic variation interact and how environmental factors modulate their effects. Moreover, the challenging question lying ahead of us is how genetic and environmental factors translate to molecular disease pathways. New approaches, including animal studies and in vitro disease modeling, as well as innovative real-world environment assessment methods, will help to understand the complex etiology of schizophrenia.