Layla Kassem

Microduplications of 16p11.2 are associated with schizophrenia.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 × 10−5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 × 10−7), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10−7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10−13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

Two variants in Ankyrin 3 ( ANK3 ) are independent genetic risk factors for bipolar disorder

Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340 kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1–4 (P=0.05; odds ratio (OR)=1.24) and German (P=0.0006; OR=1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P=0.017; OR=1.38). A random-effects meta-analysis of all three samples was significant (P=3 × 10−6; OR=1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P=0.0001; OR=1.70), and similar ORs in the NIMH 1–4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P=1.7 × 10−5; OR=1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.

Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined sample of ∼14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10−11 level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case–control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.

Family-based association of FKBP5 in bipolar disorder.

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic–pituitary–adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.

The International Consortium on Lithium Genetics (ConLiGen): An Initiative by the NIMH and IGSLI to Study the Genetic Basis of Response to Lithium Treatment

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic ‘fashions’, and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts.

Nested association between genetic variation in tryptophan hydroxylase II, bipolar affective disorder, and suicide attempts

BACKGROUND Bipolar affective disorder (BPAD) is a common mental illness that is strongly associated with suicide. Suicidal behavior is thought to result from an interaction of genetic, neurobiological, and psychosocial factors and tends to cluster in families, suggesting specific familial factors distinct from those that underlie BPAD itself. Serotonin signaling has long been implicated in both BPAD and suicide, and the gene encoding the brain-expressed isoform of tryptophan hydroxlyase (TPH2) has been described. Markers in TPH2 have been implicated in suicide and major depressive disorder, but the results across studies are inconsistent. No studies have examined TPH2 in large samples of subjects with BPAD and suicide attempts (SA). We tested for a relationship between genetic variation in TPH2 and risk for BPAD and SA in a large family sample. METHODS The sample consisted of 2018 members of 670 families, ascertained through a sibling pair affected with bipolar I, bipolar II, or schizoaffective-bipolar disorder and diagnosed under DSM-III/IV criteria. Three single nucleotide polymorphisms representing the common haplotypes spanning TPH2 were analyzed. RESULTS Single-marker analysis failed to detect significant genetic association with BPAD or SA, but the number of informative families was small. Haplotype analysis showed significant association with both BPAD and SA, and the same haplotype was significantly associated with both BPAD and SA in a replication sample. Case-only analysis, stratified by SA, suggested that TPH2 was not an independent genetic risk factor for SA in this sample. CONCLUSIONS The TPH2 might contribute to the risk of both BPAD and SA in families with BPAD. Further studies are needed to uncover the functional genetic variation that accounts for the observed associations.

Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Objective The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Familiality of Polarity at Illness Onset in Bipolar Affective Disorder

OBJECTIVE Bipolar affective disorder is clinically heterogeneous, and clinical features that run in families may help define more homogeneous phenotypes. The authors sought to establish whether polarity at illness onset, which is related to severity and course, is a familial feature of bipolar affective disorder. METHOD The authors studied 971 subjects from 507 families ascertained through sibling pairs with bipolar I or schizoaffective bipolar disorder. Self-reported ages at onset of mania and major depression were used to code polarity at onset as manic, major depressive, or both (mania and major depression in the same onset year). Familial clustering was estimated by using mixed-effects regression analysis, and the relationship between polarity at onset and several other clinical features was assessed. As a preliminary test of genetic validity, the authors assessed the impact of polarity at onset on genetic linkage findings previously detected in this sample. RESULTS Polarity at onset was significantly familial in this sample. This largely reflected relative pairs concordant for mania at onset, which occurred significantly more frequently than would be expected by chance. Mania at onset substantially increased the genetic linkage signal on chromosome 16p (maximum lod score=4.5) but had no effect on linkage to chromosome 6q. Mania at onset occurred at a later age on average than major depression at onset and was less likely to be complicated by panic attacks or alcoholism. CONCLUSIONS Polarity at illness onset is a familial feature of bipolar affective disorder and is associated with important clinical indicators, which may help define more homogeneous subtypes of bipolar affective disorder.

Sequence variation in DOCK9 and heterogeneity in bipolar disorder.

Background Linkage of bipolar disorder to a broad region on chromosome 13q has been supported in several studies including a meta-analysis on genome scans. Subsequent reports have shown that variations in the DAOA (G72) locus on 13q33 display association with bipolar disorder but these may not account for all of the linkage evidence in the region. Objective To identify additional susceptibility loci on 13q32-q33 by linkage disequilibrium mapping and explore the impact of phenotypic heterogeneity on association. Methods In the initial phase, 98 single nucleotide polymorphism (SNPs) located on 13q32-q33 were genotyped on 285 probands with bipolar disorder and their parents were drawn from families in the NIMH Genetics Initiative consortium for bipolar disorder (NIMH1-4) and two other series. Fine scale mapping using one family series (NIMH1-2) as the test sample was targeted on a gene that displayed the highest evidence of association. A secondary analysis of familial component phenotypes of bipolar disorder was conducted. Results Three of seven SNPs in DOCK9, a gene that encodes an activator of the Rho-GTPase Cdc42, showed significant excess allelic transmission (P=0.0477−0.00067). Fine scale mapping on DOCK9 yielded evidence of association at nine SNPs in the gene (P=0.02−0.006). Follow-up tests detected excess transmission of the same allele of rs1340 in two out of three other sets of families. The association signals were largely attributable to maternally transmitted alleles (rs1927568: P=0.000083; odds ratio=3.778). A secondary analysis of familial component phenotypes of bipolar disorder detected significant association across multiple DOCK9 markers for racing thoughts, psychosis, delusion during mania and course of illness indicators. Conclusion These results suggest that DOCK9 contributes to both risk and increased illness severity in bipolar disorder. We found evidence for the effect of phenotypic heterogeneity on association. To our knowledge this is the first report to implicate DOCK9 or the Rho-GTPase pathway in the etiology of bipolar disorder.

Neurocognitive functioning in euthymic patients with bipolar disorder and unaffected relatives: A review of the literature.

BACKGROUND Neurocognitive deficits are present in bipolar disorder (BD) patients and their unaffected (nonbipolar) relatives, but it is not clear which domains are most often impaired and the extent of the impairment resulting from shared genetic factors. In this literature review, we address these issues and identify specific neurocognitive tasks most sensitive to cognitive deficits in patients and unaffected relatives. METHOD We conducted a systematic review in Web of Science, PubMed/Medline and PsycINFO databases. RESULTS Fifty-one articles assessing cognitive functioning in BD patients (23 studies) and unaffected relatives (28 studies) were examined. Patients and, less so, relatives show impairments in attention, processing speed, verbal learning/memory, and verbal fluency. CONCLUSION Studies were more likely to find impairment in patients than relatives, suggesting that some neurocognitive deficits may be a result of the illness itself and/or its treatment. However, small sample sizes, differences among relatives studied (e.g., relatedness, diagnostic status, age), and differences in assessment instruments may contribute to inconsistencies in reported neurocognitive performance among relatives. Additional studies addressing these issues are needed.