Despite the need for more effective treatments for psychiatric disorders, development of new medications has stalled. Here we discuss the promise of personalized medicine in developing more ...efficacious and individualized pharmacotherapies that take into account genetic variation and target groups of patients who share biology, not just symptoms.
Aneuploidy syndromes impact multiple organ systems but understanding of tissue-specific aneuploidy effects remains limited-especially for the comparison between peripheral tissues and relatively ...inaccessible tissues like brain. Here, we address this gap in knowledge by studying the transcriptomic effects of chromosome X, Y, and 21 aneuploidies in lymphoblastoid cell lines, fibroblasts and iPSC-derived neuronal cells (LCLs, FCL, and iNs, respectively). We root our analyses in sex chromosome aneuploidies, which offer a uniquely wide karyotype range for dosage effect analysis. We first harness a large LCL RNA-seq dataset from 197 individuals with one of 6 sex chromosome dosages (SCDs: XX, XXX, XY, XXY, XYY, and XXYY) to i) validate theoretical models of SCD sensitivity and ii) define an expanded set of 41 genes that show obligate dosage sensitivity to SCD and are all in
(i.e., reside on the X or Y chromosome). We then use multiple complementary analyses to show that
effects of SCD in LCLs are preserved in both FCLs (n = 32) and iNs (n = 24), whereas
effects (i.e., those on autosomal gene expression) are mostly not preserved. Analysis of additional datasets confirms that the greater cross-cell type reproducibility of
vs.
effects is also seen in trisomy 21 cell lines. These findings i) expand our understanding of X, Y, and 21 chromosome dosage effects on human gene expression and ii) suggest that LCLs may provide a good model system for understanding
effects of aneuploidy in harder-to-access cell types.
Association of the G72/G30 locus with schizophrenia and bipolar disorder has now been reported in several studies. The G72/G30 locus may be one of several that account for the evidence of linkage ...that spans a broad region of chromosome 13q. However, the story of G72/G30 is complex. Our meta-analysis of published association studies shows highly significant evidence of association between nucleotide variations in the G72/G30 region and schizophrenia, along with compelling evidence of association with bipolar disorder. But the associated alleles and haplotypes are not identical across studies, and some strongly associated variants are located ∼50 kb telomeric of G72. Interestingly, G72 and G30 are transcribed in opposite directions; hence, their transcripts could cross-regulate translation. A functional native protein and functional motifs for G72 or G30 remain to be demonstrated. The interaction of G72 with
d-amino acid oxidase, itself of interest as a modulator of
N-methyl-
d-aspartate receptors through regulation of
d-serine levels, has been reported in one study and could be a key functional link that deserves further investigation. The association findings in the G72/G30 region, among the most compelling in psychiatry, may expose an important molecular pathway involved in susceptibility to schizophrenia and bipolar disorder.
ObjectiveIndirect evidence suggests that common genetic variation contributes to individual differences in antidepressant efficacy among individuals with major depressive disorder, but previous ...studies may have been underpowered to detect these effects.MethodA meta-analysis was performed on data from three genome-wide pharmacogenetic studies (the Genome-Based Therapeutic Drugs for Depression GENDEP project, the Munich Antidepressant Response Signature MARS project, and the Sequenced Treatment Alternatives to Relieve Depression STAR*D study), which included 2,256 individuals of Northern European descent with major depressive disorder, and antidepressant treatment outcomes were prospectively collected. After imputation, 1.2 million single-nucleotide polymorphisms were tested, capturing common variation for association with symptomatic improvement and remission after up to 12 weeks of antidepressant treatment.ResultsNo individual association met a genome-wide threshold for statistical significance in the primary analyses. A polygenic score derived from a meta-analysis of GENDEP and MARS participants accounted for up to approximately 1.2% of the variance in outcomes in STAR*D, suggesting a weakly concordant signal distributed over many polymorphisms. An analysis restricted to 1,354 individuals treated with citalopram (STAR*D) or escitalopram (GENDEP) identified an intergenic region on chromosome 5 associated with early improvement after 2 weeks of treatment.ConclusionsDespite increased statistical power accorded by meta-analysis, the authors identified no reliable predictors of antidepressant treatment outcome, although they did identify modest, direct evidence that common genetic variation contributes to individual differences in antidepressant response.
While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution ...of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 1.4,16.0, p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 1.7,22.6, p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 1.5,16.8, p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.
► Strong association of rare de novo CNVs with bipolar disorder ► Rare de novo CNVs influence age at disease onset in bipolar disorder ► Replication of earlier findings of a high frequency of de novo CNVs in schizophrenia
The rapid progress in psychiatric genetics over the past 10 years, while exciting from a research perspective, has not yet had an impact on clinical practice. How will we really be able to put ...genetics to work in the psychiatric clinic? This overview will attempt to answer this question. A survey of widely used methods and major study designs highlights key findings that have emerged so far. These findings inform a broad conceptual model of how genetic risk may act to influence dimensions of psychopathology and clinical presentations. The overview concludes with highlights of some of the most clinically relevant findings to date and their implications for psychiatric practice in the near future.
As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to ...dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.
The genetics of bipolar disorder Gordovez, Francis James A; McMahon, Francis J
Molecular psychiatry,
03/2020, Volume:
25, Issue:
3
Journal Article
Peer reviewed
Bipolar disorder (BD) is one of the most heritable mental illnesses, but the elucidation of its genetic basis has proven to be a very challenging endeavor. Genome-Wide Association Studies (GWAS) have ...transformed our understanding of BD, providing the first reproducible evidence of specific genetic markers and a highly polygenic architecture that overlaps with that of schizophrenia, major depression, and other disorders. Individual GWAS markers appear to confer little risk, but common variants together account for about 25% of the heritability of BD. A few higher-risk associations have also been identified, such as a rare copy number variant on chromosome 16p11.2. Large scale next-generation sequencing studies are actively searching for other alleles that confer substantial risk. As our understanding of the genetics of BD improves, there is growing optimism that some clear biological pathways will emerge, providing a basis for future studies aimed at molecular diagnosis and novel therapeutics.
Treatment-resistant depression (TRD) is a severe form of major depressive disorder (MDD) with substantial public health impact and poor treatment outcome. Treatment outcome in MDD is significantly ...heritable, but genome-wide association studies have failed to identify replicable common marker alleles, suggesting a potential role for uncommon variants. Here we investigated the hypothesis that uncommon, putatively functional genetic variants are associated with TRD. Whole-exome sequencing data was obtained from 182 TRD cases and 2021 psychiatrically healthy controls. After quality control, the remaining 149 TRD cases and 1976 controls were analyzed with tests designed to detect excess burdens of uncommon variants. At the gene level, 5 genes, ZNF248, PRKRA, PYHIN1, SLC7A8, and STK19 each carried exome-wide significant excess burdens of variants in TRD cases (q < 0.05). Analysis of 41 pre-selected gene sets suggested an excess of uncommon, functional variants among genes involved in lithium response. Among the genes identified in previous TRD studies, ZDHHC3 was also significant in this sample after multiple test correction. ZNF248 and STK19 are involved in transcriptional regulation, PHYIN1 and PRKRA are involved in immune response, SLC7A8 is associated with thyroid hormone transporter activity, and ZDHHC3 regulates synaptic clustering of GABA and glutamate receptors. These results implicate uncommon, functional alleles in TRD and suggest promising novel targets for future research.
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