August G. Wang

Large recurrent microdeletions associated with schizophrenia.

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Brain expressed microRNAs implicated in schizophrenia etiology.

Background Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. Methodology/Principal Findings We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia. Conclusions/Significance We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.

Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder: An association study†

Recent meta‐analyses of the methylenetetrahydrofolate reductase gene (MTHFR) have suggested association between two of its functional single gene polymorphisms (SNPs; C677T and A1298C) and schizophrenia. Studies have also suggested association between MTHFR C677T and A1298C variation and bipolar disorder. In a replication attempt the MTHFR C677T and A1298C SNPs were analyzed in three Scandinavian schizophrenia case‐control samples. In addition, Norwegian patients with bipolar disorder were investigated. There were no statistically significant allele or genotype case‐control differences. The present Scandinavian results do not verify previous associations between the putative functional MTHFR gene polymorphisms and schizophrenia or bipolar disorder. However, when combined with previous studies in meta‐analyses there is still evidence for association between the MTHFR C677T polymorphism and schizophrenia. Additional studies are warranted to shed further light on these relationships.

The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: A multi-centre case–control study and meta-analysis†‡

Serotonin (5‐hydroxytryptamin; 5‐HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5‐monooxygenase; TPH) is the rate‐limiting enzyme in the biosynthesis of 5‐HT, and sequence variation in intron 6 of the TPH1 gene has been associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (P = 0.019). However there were no differences in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (P = 0.84). A systematic literature review and meta‐analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07–1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I2 = 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR = 0.96 [0.80–1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and Asian populations. In addition, the data at hand suggest that the locus contributes to the liability of psychiatric disorders characterized by elevated suicidal rates, rather than affecting suicidal behavior of individuals suffering from a psychiatric disorder.

A haplotype-based study of lithium responding patients with bipolar affective disorder on the Faroe Islands.

The Faroe Islands are a small group of islands in the North Atlantic Ocean, situated between Norway, Iceland and Scotland. The origin of the population is thought to be a mixture of Norwegian, Danish and British. The islands were populated at the same time as Iceland, i.e. around 1100 years ago, and the size of the population was around, and occasionally below, 4000 inhabitants until 1800, after which it increased to its present-day level of around 45,000. The population is descended from Scandinavian and British ancestors. Because of the low number of founders and small size for many centuries, the Faroese population is perhaps the most valuable European population for genetic mapping of complex disease genes. The present study searched for haplotype sharing on chromosome 18 among eight lithium responding patients with bipolar affective disorder related, on average, 6.2 generations ago, using 30 DNA markers. In order to obtain as homogeneous a sample as possible, strict inclusion criteria based on severity of phenotype, geography and treatment response, were applied. Evidence suggestive of increased haplotype sharing on the distal part of chromosome 18q23 in the region implicated by Freimer and co-workers was found. However, methods of genetic analysis which might provide a conclusive result are not yet available.

Short-term and long-term effects of psychosocial therapy for people after deliberate self-harm: a register-based, nationwide multicentre study using propensity score matching

BACKGROUND Although deliberate self-harm is a strong predictor of suicide, evidence for effective interventions is missing. The aim of this study was to examine whether psychosocial therapy after self-harm was linked to lower risks of repeated self-harm, suicide, and general mortality. METHODS In this matched cohort study all people who, after deliberate self-harm, received a psychosocial therapy intervention at suicide prevention clinics in Denmark during 1992-2010 were compared with people who did not receive the psychosocial therapy intervention after deliberate self-harm. We applied propensity score matching with a 1:3 ratio and 31 matching factors, and calculated odds ratios for 1, 5, 10, and 20 years of follow-up. The primary endpoints were repeated self-harm, death by suicide, and death by any cause. FINDINGS 5678 recipients of psychosocial therapy (followed up for 42·828 person-years) were matched with 17,034 individuals with no psychosocial therapy in a 1:8 ratio. During 20 year follow-up, 937 (16·5%) recipients of psychosocial therapy repeated the act of self-harm, and 391 (6·9%) died, 93 (16%) by suicide. The psychosocial therapy intervention was linked to lower risks of self-harm than was no psychosocial therapy (odds ratio [OR] 0·73, 95% CI 0·65-0·82) and death by any cause (0·62, 0·47-0·82) within a year. Long-term effects were identified for repeated self-harm (0·84, 0·77-0·91; absolute risk reduction [ARR] 2·6%, 1·5-3·7; numbers needed to treat [NNT] 39, 95% CI 27-69), deaths by suicide (OR 0·75, 0·60-0·94; ARR 0·5%, 0·1-0·9; NNT 188, 108-725), and death by any cause (OR 0·69, 0·62-0·78; ARR 2·7%, 2·0-3·5; NNT 37, 29-52), implying that 145 self-harm episodes and 153 deaths, including 30 deaths by suicide, were prevented. INTERPRETATION Our findings show a lower risk of repeated deliberate self-harm and general mortality in recipients of psychosocial therapy after short-term and long-term follow-up, and a protective effect for suicide after long-term follow-up, which favour the use of psychosocial therapy interventions after deliberate self-harm. FUNDING Danish Health Insurance Foundation; the Research Council of Psychiatry, Region of Southern Denmark; the Research Council of Psychiatry, Capital Region of Denmark; and the Strategic Research Grant from Health Sciences, Capital Region of Denmark.

Highly discrepant proportions of female and male Scandinavian and British Isles ancestry within the isolated population of the Faroe Islands

The Faroe Islands in the North Atlantic Ocean are inhabited by a small population, whose origin is thought to date back to the Viking Age. Historical, archaeological and linguistic evidence indicates that the present population of the Faroe Islands may have a mixture of Scandinavian and British Isles ancestry. In the present study we used 122 new and 19 previously published hypervariable region I sequences of the mitochondrial control region to analyse the genetic diversity of the Faroese population and compare it with other populations in the North Atlantic region. The analyses suggested that the Faroese mtDNA pool has been affected by genetic drift, and is among the most homogenous and isolated in the North Atlantic region. This will have implications for attempts to locate genes for complex disorders. To obtain estimates of Scandinavian vs British Isles ancestry proportions, we applied a frequency-based admixture approach taking private haplotypes into account by the use of phylogenetic information. While previous studies have suggested an excess of Scandinavian ancestry among the male settlers of the Faroe Islands, the current study indicates an excess of British Isles ancestry among the female settlers of the Faroe Islands. Compared to other admixed populations of the North Atlantic region, the population of the Faroe Islands appears to have the highest level of asymmetry in Scandinavian vs British Isles ancestry proportions among female and male settlers of the archipelago.

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

Panic disorder (PD) is a mental disorder with recurrent panic attacks that occur spontaneously and are not associated to any particular object or situation. There is no consensus on what causes PD. However, it is recognized that PD is influenced by environmental factors, as well as genetic factors. Despite a significant hereditary component, genetic studies have only been modestly successful in identifying genes of importance for the development of PD. In this study, we conducted a genome-wide scan using microsatellite markers and PD patients and control individuals from the isolated population of the Faroe Islands. Subsequently, we conducted a fine mapping, which revealed the amiloride-sensitive cation channel 1 (ACCN1) located on chromosome 17q11.2-q12 as a potential candidate gene for PD. The further analyses of the ACCN1 gene using single-nucleotide polymorphisms (SNPs) revealed significant association with PD in an extended Faroese case–control sample. However, analyses of a larger independent Danish case–control sample yielded no substantial significant association. This suggests that the possible risk alleles associated in the isolated population are not those involved in the development of PD in a larger outbred population.

Preventing repetition of attempted suicide—II. The Amager Project, a randomized controlled trial

Repetition after attempted suicide is high but only few effect studies have been carried out. The Baerum Model from Norway offers practical and affordable intervention for those not being offered psychiatric treatment. During a period from 2005–2007, all attempted suicide patients except those with major psychiatric diagnoses (schizophrenia, bipolar disorder, severe/psychotic depression), were offered participation. The intervention group received the OPAC programme (outreach, problem solving, adherence, continuity) and the control group received treatment as usual (TAU). The intervention period was 6 months. After this intervention period, all patients were followed passively for an extra 6 months. The design was an intent-to-treat one. The outcomes were: 1) repetition of attempted suicide or suicide, and 2) total number of suicidal acts. A total of 200 patients were offered participation, 67 refused. Of the 133 participants, 69 were randomized to the OPAC programme and 64 to the (non-intervention) control group. Four in each group dropped out after initial participation. There was a significant lower proportion who repeated a suicide attempt the intervention group (proportion 8.7%) than in the control group (proportion 21.9%) and the number of repetitive acts was also significant lower (eight repetitions in the intervention group vs. 22 in the control group). In conclusion, our findings suggest a protective effect of the OPAC programme on the proportion who repeated a suicide attempt and on the total number of repetitions during the follow-up.

Suicide and mental illness in parents and risk of suicide in offspring : A birth cohort study

BackgroundA family history of completed suicide and psychiatric illness has been identified as risk factors for suicide.AimsTo examine the risk of offspring suicide in relation to parental history of suicide and other parental risk factors.MethodThe study population consisted of 7,177 adult offspring born 1959–1961 and their parents from the Copenhagen Perinatal Cohort. Cohort members and their parents who had committed suicide were identified in the Danish Causes of Death Registry (follow-up until December 31, 2005), while information on psychiatric hospitalisation history was obtained from the Danish Psychiatric Central Research Register.ResultsForty-eight cohort members, 77 mothers and 133 fathers had committed suicide during the follow-up. Independent of parental psychiatric illness and social status, parental suicide significantly increased suicide risk in offspring (hazard ratio 4.40 with 95% CI 1.81–10.69). A stronger effect of parental suicide was observed in offspring without a history of psychiatric hospitalisation.ConclusionParental history of suicide is a risk factor for suicide in offspring, but primarily in offspring without psychiatric hospitalisation.