The human brain is the outcome of innumerable evolutionary processes; the systems genetics of psychiatric disorders could bear their signatures. On this basis, we analyzed five psychiatric disorders, ...attention deficit hyperactivity disorder, autism spectrum disorder (ASD), bipolar disorder, major depressive disorder, and schizophrenia (SCZ), using GWAS summary statistics from the Psychiatric Genomics Consortium. Machine learning-derived scores were used to investigate two natural-selection scenarios: complete selection (loci where a selected allele reached fixation) and incomplete selection (loci where a selected allele has not yet reached fixation). ASD GWAS results positively correlated with incomplete-selection (p = 3.53*10-4). Variants with ASD GWAS p<0.1 were shown to have a 19%-increased probability to be in the top-5% for incomplete-selection score (OR = 1.19, 95%CI = 1.11-1.8, p = 9.56*10-7). Investigating the effect directions of minor alleles, we observed an enrichment for positive associations in SNPs with ASD GWAS p<0.1 and top-5% incomplete-selection score (permutation p<10-4). Considering the set of these ASD-positive-associated variants, we observed gene-expression enrichments for brain and pituitary tissues (p = 2.3*10-5 and p = 3*10-5, respectively) and 53 gene ontology (GO) enrichments, such as nervous system development (GO:0007399, p = 7.57*10-12), synapse organization (GO:0050808, p = 8.29*10-7), and axon guidance (GO:0007411, p = 1.81*10-7). Previous genetic studies demonstrated that ASD positively correlates with childhood intelligence, college completion, and years of schooling. Accordingly, we hypothesize that certain ASD risk alleles were under positive selection during human evolution due to their involvement in neurogenesis and cognitive ability.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
5HTTLPR, which is the trivial name for a variable number of tandem repeats (VNTR) polymorphism mapped to the 5′ region of the
SLC6A4
(serotonin transporter protein) gene, is one of the most studied ...variants with respect to psychiatric traits. It is also widely studied in the context of intermediate phenotypes such as neuroimaging measures, and gene-by-environment interaction, the latter generally in the context of affective and anxiety phenotypes. In this article, the author discusses the importance of the variant in the context of a population genetics article published in Human Genetics sixteen years ago.
Objective:Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently ...comorbid with other mental disorders, such as major depressive disorder.Methods:Using one of the world’s largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale GAD-2, N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis.Results:The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75).Conclusions:This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.
Results from Genome-Wide Association Studies (GWAS) have shown that complex diseases are often affected by many genetic variants with small or moderate effects. Identifications of these risk variants ...remain a very challenging problem. There is a need to develop more powerful statistical methods to leverage available information to improve upon traditional approaches that focus on a single GWAS dataset without incorporating additional data. In this paper, we propose a novel statistical approach, GPA (Genetic analysis incorporating Pleiotropy and Annotation), to increase statistical power to identify risk variants through joint analysis of multiple GWAS data sets and annotation information because: (1) accumulating evidence suggests that different complex diseases share common risk bases, i.e., pleiotropy; and (2) functionally annotated variants have been consistently demonstrated to be enriched among GWAS hits. GPA can integrate multiple GWAS datasets and functional annotations to seek association signals, and it can also perform hypothesis testing to test the presence of pleiotropy and enrichment of functional annotation. Statistical inference of the model parameters and SNP ranking is achieved through an EM algorithm that can handle genome-wide markers efficiently. When we applied GPA to jointly analyze five psychiatric disorders with annotation information, not only did GPA identify many weak signals missed by the traditional single phenotype analysis, but it also revealed relationships in the genetic architecture of these disorders. Using our hypothesis testing framework, statistically significant pleiotropic effects were detected among these psychiatric disorders, and the markers annotated in the central nervous system genes and eQTLs from the Genotype-Tissue Expression (GTEx) database were significantly enriched. We also applied GPA to a bladder cancer GWAS data set with the ENCODE DNase-seq data from 125 cell lines. GPA was able to detect cell lines that are biologically more relevant to bladder cancer. The R implementation of GPA is currently available at http://dongjunchung.github.io/GPA/.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder ...Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits' PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.
Studies on genetic-epigenetic interactions, including the mapping of methylation quantitative trait loci (mQTLs) and haplotype-dependent allele-specific DNA methylation (hap-ASM), have become a major ...focus in the post-genome-wide-association-study (GWAS) era. Such maps can nominate regulatory sequence variants that underlie GWAS signals for common diseases, ranging from neuropsychiatric disorders to cancers. Conversely, mQTLs need to be filtered out when searching for non-genetic effects in epigenome-wide association studies (EWAS). Sequence variants in CCCTC-binding factor (CTCF) and transcription factor binding sites have been mechanistically linked to mQTLs and hap-ASM. Identifying these sites can point to disease-associated transcriptional pathways, with implications for targeted treatment and prevention.
Background We report a genome-wide association study (GWAS) of two populations, African-American and European-American (AA, EA) for opioid dependence (OD) in three sets of subjects, to identify ...pathways, genes, and alleles important in OD risk. Methods The design employed three phases (on the basis of separate sample collections). Phase 1 included our discovery GWAS dataset consisting of 5697 subjects (58% AA) diagnosed with opioid and/or other substance dependence and control subjects. Subjects were genotyped with the Illumina OmniQuad microarray, yielding 890,000 single nucleotide polymorphisms (SNPs) suitable for analysis. Additional genotypes were imputed with the 1000 Genomes reference panel. Top-ranked findings were further evaluated in Phase 2 by incorporating information from the publicly available Study of Addiction: Genetics and Environment dataset, with GWAS data from 4063 subjects (32% AA). In Phase 3, the most significant SNPs from Phase 2 were genotyped in 2549 independent subjects (32% AA). Analyses were performed with case-control and ordinal trait designs. Results Most significant results emerged from the AA subgroup. Genome-wide-significant associations ( p < 5.0 × 10−8 ) were observed with SNPs from multiple loci– KCNG2* rs62103177 was most significant after combining results from datasets in every phase of the study. The most compelling results were obtained with genes involved in potassium signaling pathways (e.g., KCNC1 and KCNG2 ). Pathway analysis also implicated genes involved in calcium signaling and long-term potentiation. Conclusions This is the first study to identify risk variants for OD with GWAS. Our results strongly implicate risk pathways and provide insights into novel therapeutic and prevention strategies and might biologically bridge OD and other non–substance dependence psychiatric traits where similar pathways have been implicated.
Brain function and cognitive performance differ between men and women in some measures. The phenotypic variation may be partially due to sex differences in epigenomes and transcriptomes in specific ...brain regions e.g. the prefrontal cortex (PFC). Genome-wide DNA methylation and gene expression were examined in postmortem PFC of 32 males and 14 females (all were Caucasians) using Illumina's 450K Methylation and HT-12 v4 Gene Expression BeadChips, respectively. Multiple linear regression, Pearson correlation and DAVID functional annotation analyses were applied to investigate sex-biased DNA methylation and gene expression, DNA methylation-gene expression correlation and gene ontology (GO) annotations overrepresented by differentially methylated and expressed genes. A total of 22 124 CpGs showed differential methylation between males and females (2.6 × 10(-38) ≤ Pnominal ≤ 0.05), and the P-values of 8357 CpGs withstood multiple-testing correction (q < 0.05). A total of 1489 genes showed differential expression between males and females (4.1 × 10(-36) ≤ Pnominal ≤ 0.05), and the P-values of 35 genes survived multiple-testing correction (q < 0.05). A significant correlation (Pcorrelation < 0.05) was observed between methylation levels of 585 differentially methylated CpGs (Pnominal ≤ 0.05) and expression levels of 188 differentially expressed host genes (Pnominal < 0.05). The GO terms enriched by these 188 genes (134 on autosomes and 54 on sex chromosomes) were assigned to 24 clusters, and 33 genes involved in the top cluster (enrichment score: 4.7) mainly participate in ribosome structure and function, RNA binding and protein translation. This study demonstrated sex-specific methylomic and transcriptomic profiles in the human PFC. Our findings suggest that sex-biased DNA methylation and gene expression could be either the cause or consequence of differential brain development between males and females.
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