Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder.

Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk.

Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes.

Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10(-7)). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.

Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, IFT27 and parvalbumin.

We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case-control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5 Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P = 4.69 × 10(-4)). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P = 1.42 × 10(-5)). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P = 8.89 × 10(-6)). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P = 3.43 × 10(-4)). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P = 1.76 × 10(-6)). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region.

Premenstrual mood symptoms: study of familiality and personality correlates in mood disorder pedigrees.

We sought to determine whether premenstrual mood symptoms exhibit familial aggregation in bipolar disorder or major depression pedigrees. Two thousand eight hundred seventy-six women were interviewed with the Diagnostic Interview for Genetic Studies as part of either the NIMH Genetics Initiative Bipolar Disorder Collaborative study or the Genetics of Early Onset Major Depression (GenRED) study and asked whether they had experienced severe mood symptoms premenstrually. In families with two or more female siblings with bipolar disorder (BP) or major depressive disorder (MDD), we examined the odds of having premenstrual mood symptoms given one or more siblings with these symptoms. For the GenRED MDD sample we also assessed the impact of personality as measured by the NEO-FFI. Premenstrual mood symptoms did not exhibit familial aggregation in families with BP or MDD. We unexpectedly found an association between high NEO openness scores and premenstrual mood symptoms, but neither this factor, nor NEO neuroticism influenced evidence for familial aggregation of symptoms. Limitations include the retrospective interview, the lack of data on premenstrual dysphoric disorder, and the inability to control for factors such as medication use.

Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder.

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.

Genetics of recurrent early-onset major depression (GenRED): final genome scan report.

OBJECTIVE: The authors carried out a genomewide linkage scan to identify chromosomal regions likely to contain genes that contribute to susceptibility to recurrent early-onset major depressive disorder, the form of the disorder with the greatest reported risk to relatives of index cases. METHOD: Microsatellite DNA markers were studied in 656 families with two or more such cases (onset before age 31 in probands and age 41 in other relatives), including 1,494 informative "all possible" affected relative pairs (there were 894 independent affected sibling pairs). Analyses included a primary multipoint allele-sharing analysis (with ALLEGRO) and a secondary logistic regression analysis taking the sex of each relative pair into account (male-male, male-female, female-female). RESULTS: Genomewide suggestive evidence for linkage was observed on chromosome 15q25-q26 (at 105.4 centimorgans [cM]). The authors previously reported genomewide significant linkage in this region in the first 297 families. In the secondary analysis, after empirical genomewide correction for multiple testing, suggestive linkage results were observed on chromosome 17p12 (28.0 cM, excess sharing in male-male and male-female pairs) and on chromosome 8p22-p21.3 (25.1 cM, excess sharing in male-male pairs). CONCLUSIONS: These regions of chromosomes 15q, 17p, and 8p might contain genes that contribute to susceptibility to major depression and related disorders. Evidence for linkage has been reported independently in the same regions of chromosome 15q for major depression and of chromosome 8p for related personality traits.

Genetics of recurrent early-onset major depression (GenRED): significant linkage on chromosome 15q25-q26 after fine mapping with single nucleotide polymorphism markers.

OBJECTIVE: The authors studied a dense map of single nucleotide polymorphism (SNP) DNA markers on chromosome 15q25-q26 to maximize the informativeness of genetic linkage analyses in a region where they previously reported suggestive evidence for linkage of recurrent early-onset major depressive disorder. METHOD: In 631 European-ancestry families with multiple cases of recurrent early-onset major depressive disorder, 88 SNPs were genotyped, and multipoint allele-sharing linkage analyses were carried out. Marker-marker linkage disequilibrium was minimized, and a simulation study with founder haplotypes from these families suggested that linkage scores were not inflated by linkage disequilibrium. RESULTS: The dense SNP map increased the information content of the analysis from around 0.7 to over 0.9. The maximum evidence for linkage was the Z likelihood ratio score statistic of Kong and Cox (Z(LR))=4.69 at 109.8 cM. The exact p value was below the genomewide significance threshold. By contrast, in the genome scan with microsatellite markers at 9 cM spacing, the maximum Z(LR) for European-ancestry families was 3.43 (106.53 cM). It was estimated that the linked locus or loci in this region might account for a 20% or less populationwide increase in risk to siblings of cases. CONCLUSIONS: This region has produced modestly positive evidence for linkage to depression and related traits in other studies. These results suggest that DNA sequence variations in one or more genes in the 15q25-q26 region can increase susceptibility to major depression and that efforts are warranted to identify these genes.

A comparison of the familiality of chronic depression in recurrent early-onset depression pedigrees using different definitions of chronicity.

BACKGROUND: The study of chronicity in the course of major depression has been complicated by varying definitions of this illness feature. Because familial clustering is one component of diagnostic validity we compared family clustering of chronicity as defined in the DSM-IV to that of chronicity determined by an assessment of lifetime course of depressive illness. METHODS: In 1750 affected subjects from 652 families recruited for a genetic study of recurrent, early-onset depression, we applied several definitions of chronicity. Odds ratios were determined for the likelihood of chronicity in a proband predicting chronicity in an affected relative. RESULTS: There was greater family clustering of chronicity as determined by assessment of lifetime course (OR=2.54) than by DSM-IV defined chronic major depressive episode (MDE) (OR=1.93) or dysthymic disorder (OR=1.76). In families with probands who had preadolescent onset of MDD, familiality was increased by all definitions, with a much larger increase observed for chronicity by lifetime course (ORs were 6.14 for lifetime chronicity, 2.43 for chronic MDE, and 3.42 for comorbid dysthymic disorder). Agreement between these definitions of chronicity was only fair. LIMITATIONS: The data used to determine chronicity were collected retrospectively and not blindly to relatives' status, and assessment of lifetime course was based on global clinical impressions gathered during a semi-structured diagnostic interview. Also, it can be difficult to determine whether individuals with recurrent major depressive episodes who frequently experience long periods of low grade depressive symptoms meet the strict timing requirements of DSM-IV dysthymic disorder. CONCLUSIONS: An assessment of lifetime symptom course identifies a more familial, and thus possibly a more valid, type of chronic depression than the current DSM-IV categories which are defined in terms of particular cross-sectional features of illness.

Investigating the role of p11 (S100A10) sequence variation in susceptibility to major depression.

Recent evidence suggests a potential role for the p11 gene in conferring risk to depressive disorders. p11 has been shown to influence serotonergic transmission, and its expression was found to be reduced in a mouse model of depression, as well as in post-mortem brain tissue from major depressive disorder (MDD) cases. In the present study, we tested for rare variants in p11 by resequencing promoter, exonic and flanking intronic regions in 176 MDD cases and 176 matched controls. We also assessed common variation by genotyping eight single nucleotide polymorphisms (SNPs), seven tag SNPs and one found through resequencing, in 641 cases and 650 controls. Resequencing revealed nine novel rare variants, including a missense mutation (Asp60Glu) observed in one case and one control, and four variants that occurred only in cases and not controls. The number of rare variants in cases did not exceed that expected by chance for the length of sequence analyzed, and also was not significantly greater than that observed in controls. Resequencing also identified two known SNPs, one (rs4845720) of which was significantly more frequent in cases than controls in the resequenced sample (3.1% vs. 0.9%, P = 0.03), though not in the larger sample (3% vs. 2%, P = 0.15). None of the tag SNPs showed any evidence of association. Our results do not support a major role for either common or rare p11 SNPs with MDD. Several limitations of the study are discussed.

Familial aggregation of illness chronicity in recurrent, early-onset major depression pedigrees.

OBJECTIVE: The authors used a large sample collected for genetic studies to determine whether a chronic course of illness defines a familial clinical subtype in major depressive disorder. METHOD: A measure of lifetime chronicity of depressive symptoms (substantial mood symptoms most or all of the time) was tested for familial aggregation in 638 pedigrees from the Genetics of Recurrent Early-Onset Depression (GenRED) project. RESULTS: In subjects with chronic depression, the mean age at illness onset was lower and rates of attempted suicide, panic disorder, and substance abuse were higher than among those with nonchronic depression. Chronicity was assessed in 37.8% of affected first-degree relatives of probands with chronic depression and in 20.2% of relatives of probands with nonchronic depression. Analysis using the generalized estimating equation model yielded an odds ratio of 2.52 (SE=0.39, z=6.02, p<0.0001) for the likelihood of chronicity in a proband predicting chronicity in an affected relative. With stratification by proband age at illness onset, the odds ratio for chronicity in relatives by proband chronicity status was 6.17 (SE=2.09, z=5.35, p<0.0001) in families of probands whose illness onset was before age 13 and 1.92 (SE=0.34, z=3.72, p<0.0001) in families of probands whose illness started at age 13 or later. CONCLUSIONS: These findings suggest that chronicity of depressive symptoms is familial, especially in preadolescent-onset illness. Chronicity is also associated with other indicators of illness severity in recurrent, early-onset major depression. Further study using chronicity as a subtype in the genetic analysis of depressive illness is warranted. Refinement of the definition of chronicity in depressive illness may increase the power of such studies.

Is perinatal depression familial?

BACKGROUND: While major depressive disorder (MDD) is familial, it is not clear whether distinct familial-genetic factors influence vulnerability to depression during or after pregnancy. Here we examine familial aggregation of perinatal major depression (PND, any episode during pregnancy or the month after childbirth) and the subset of post-partum depression (PPD) in families with multiple cases of recurrent, early-onset MDD from the Genetics of Recurrent Early-Onset Depression dataset. METHODS: The dataset included 691 childbearing women who could be classified as PND (27.6%) or non-PND (NPND), of whom 328 were members of 148 sibships with two or more PND or NPND women. PND and NPND subjects were compared for differences in putative predictors. Prediction of sibling PND or PPD by the proband's history was examined using logistic regression and general estimating equation methods. RESULTS: PND was associated with fewer episodes and younger current age. Odds ratios for prediction of sibling status were significant for PND (2.28) and PPD (3.96), particularly when current age was under 46 (2.87 and 4.39, respectively). ORs for PPD were not significantly different from those for PND. The OR for PPD (3.52), but not for PND, remained significant after current age was introduced as a covariate, but not when both current age and number of episodes were included in the model. LIMITATIONS: Because detailed data were not collected for all pregnancies, we cannot determine whether current age and number of episodes mediated the observed effects due to recall bias or other factors (cohort effect, number of episodes). CONCLUSIONS: A familial component to PND, and particularly PPD, is suggested by the results. However more systematic study is needed to confirm this result. A greater understanding of both genetic and non-genetic familial factors could lead to improved prevention and clinical management.

Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans.

BACKGROUND: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, with a bipolar disorder and depression diagnosis. METHODS: The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene × sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects). RESULTS: In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p = 1.4 × 10⁻4, 2.1 × 10⁻4; p(corrected) = .03, .04) and were consistent across two large datasets. CONCLUSIONS: Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype.

Genome-wide linkage and follow-up association study of postpartum mood symptoms.

OBJECTIVE: Family studies have suggested that postpartum mood symptoms might have a partly genetic etiology. The authors used a genome-wide linkage analysis to search for chromosomal regions that harbor genetic variants conferring susceptibility for such symptoms. The authors then fine-mapped their best linkage regions, assessing single nucleotide polymorphisms (SNPs) for genetic association with postpartum symptoms. METHOD: Subjects were ascertained from two studies: the NIMH Genetics Initiative Bipolar Disorder project and the Genetics of Recurrent Early-Onset Depression. Subjects included women with a history of pregnancy, any mood disorder, and information about postpartum symptoms. In the linkage study, 1,210 women met criteria (23% with postpartum symptoms), and 417 microsatellite markers were analyzed in multipoint allele sharing analyses. For the association study, 759 women met criteria (25% with postpartum symptoms), and 16,916 SNPs in the regions of the best linkage peaks were assessed for association with postpartum symptoms. RESULTS: The maximum linkage peak for postpartum symptoms occurred on chromosome 1q21.3-q32.1, with a chromosome-wide significant likelihood ratio Z score (Z(LR)) of 2.93 (permutation p=0.02). This was a significant increase over the baseline Z(LR) of 0.32 observed at this locus among all women with a mood disorder (permutation p=0.004). Suggestive linkage was also found on 9p24.3-p22.3 (Z(LR)=2.91). In the fine-mapping study, the strongest implicated gene was HMCN1 (nominal p=0.00017), containing four estrogen receptor binding sites, although this was not region-wide significant. CONCLUSIONS: This is the first study to examine the genetic etiology of postpartum mood symptoms using genome-wide data. The results suggest that genetic variations on chromosomes 1q21.3-q32.1 and 9p24.3-p22.3 may increase susceptibility to postpartum mood symptoms.

Linkage disequilibrium mapping of a chromosome 15q25-26 major depression linkage region and sequencing of NTRK3.

BACKGROUND: We reported genome-wide significant linkage on chromosome 15q25.3-26.2 to recurrent early-onset major depressive disorder (MDD-RE). Here we present initial linkage-disequilibrium (LD) fine mapping of this signal and sequence analysis of NTRK3 (neurotrophic receptor kinase-3), a biologically plausible candidate gene. METHODS: In 300 pedigrees informative for family-based association, 1195 individuals were genotyped for 795 single nucleotide polymorphism (SNPs). We resequenced 21 exons and 7 highly conserved NTRK3 regions in 176 MDD-RE cases to test for an excess of rare functional variants and, 176 controls for case-control analysis of common variants. RESULTS: LD mapping showed nominally significant association in NTRK3, FLJ12484, RHCG, DKFZp547K1113, VPS33B, SV2B, SLCO3A1, RGMA, and MCTP2 with MDD-RE. In NTRK3, five SNPs had nominally significant p values (.035-.001). Sequence analysis revealed 35 variants (24 novel, including 9 rare exonic); the number of rare variants did not exceed chance expectation. Case-control analysis of 13 common variants showed modest nominal association of MDD-RE with rs4887379, rs6496463, and rs3825882 (p = .008, .048, and .034), which were in partial LD with four of five associated SNPs from the family-based experiment. CONCLUSIONS: Common variants in NTRK3 or other genes identified might play a role in MDD-RE. However, much larger studies are required for full evaluation of this region.

Treatment Choice in Neuroleptic Malignant Syndrome.

A literature review of patients with symptomatic neuroleptic malignant syndrome (NMS) treated with electroconvulsive therapy (ECT) yielded 26 cases, to which we add five cases. ECT was associated with a positive outcome in 26 of 31 cases with one unclear outcome and a poor outcome in four cases, including two deaths. ECT appeared to be effective in eight of nine patients previously treated with dantrolene and/or bromocriptine; no difference in time to apparent response was seen between those treated with medication first and those undergoing ECT first. The mean time to clinical response after the first ECT was 1.46 +/- 2.38 days, with 19 of 20 having a clinical response by 72 h. The possible relationship of ECT to the two deaths is discussed. Given this experience, the suggested treatment sequence is medication (dantrolene or bromocriptine) for 48 h; if no clinical response is seen, ECT should be initiated. ECT may be used earlier in response to specific clinical situations.

Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q.

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele sharing in all possible affected relative pairs with the use of the Z(lr) statistic computed by the ALLEGRO program. A secondary logistic regression analysis considered the effect of the sex of the pair as a covariate. Genomewide significant linkage was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical genomewide P=.023). The linkage was not sex specific. No other suggestive or significant results were observed in the primary analysis. The secondary analysis produced three regions of suggestive linkage, but these results should be interpreted cautiously because they depended primarily on the small subsample of 42 male-male pairs. Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility to MDD.