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A summary-statistics-based approach to examine the role of serotonin transporter promoter tandem repeat polymorphism in psychiatric phenotypes.

ABSTRACT: In genetic studies of psychiatric disorders in the pre-genome-wide association study (GWAS) era, one of the most commonly studied loci is the serotonin transporter (SLC6A4) promoter polymorphism, a 43-base-pair insertion/deletion polymorphism in the promoter region (5-HTTLPR). The genetic association signals between 5-HTTLPR and psychiatric phenotypes, however, have been inconsistent across many studies. Since the polymorphism cannot be tested via available SNP arrays, we had previously proposed an efficient machine learning algorithm to predict the genotypes of 5-HTTLPR based on the genotypes of eight nearby SNPs, which requires access to individual-level genotype and phenotype data. To utilize the advantage of publicly available GWAS summary statistics obtained from studies with very large sample sizes, we develop a GWAS summary-statistics-based approach for testing the variable number of tandem repeat (VNTR) associations with various phenotypes. We first cross-verify the accuracy of the summary-statistics-based approach for 61 phenotypes in the UK Biobank. Since we observed a strong similarity between the predicted individual-level 5-HTTLPR genotype-based approach and the summary-statistics-based approach, we applied our method to the available neurobehavioral GWAS summary statistics data obtained from large-scale GWAS. We found no genome-wide significant evidence for association between 5-HTTLPR and any of the neurobehavioral traits. We did observe, however, genome-wide significant evidence for association between this locus and human adult height, BMI, and total cholesterol. Our summary-statistics-based approach provides a systematic way to examine the role of VNTRs and related types of genetic polymorphisms in disease risk and trait susceptibility of phenotypes for which large-scale GWAS summary statistics data are available.

SUBMITTER: Majumdar A

PROVIDER: S-EPMC9091198 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRecent genome-wide association studies (GWASs) have revealed the polygenic nature of psychiatric disorders and discovered a few of single-nucleotide polymorphisms (SNPs) associated with multiple psychiatric disorders. However, the extent and pattern of pleiotropy among distinct psychiatric disorders remain not completely clear.MethodsWe analyzed 14 psychiatric disorders using summary statistics available from the largest GWASs by far. We first applied the cross-trait linkage disequilibrium score regression (LDSC) to estimate genetic correlation between disorders. Then, we performed a gene-based pleiotropy analysis by first aggregating a set of SNP-level associations into a single gene-level association signal using MAGMA. From a methodological perspective, we viewed the identification of pleiotropic associations across the entire genome as a high-dimensional problem of composite null hypothesis testing and utilized a novel method called PLACO for pleiotropy mapping. We ultimately implemented functional analysis for identified pleiotropic genes and used Mendelian randomization for detecting causal association between these disorders.ResultsWe confirmed extensive genetic correlation among psychiatric disorders, based on which these disorders can be grouped into three diverse categories. We detected a large number of pleiotropic genes including 5884 associations and 2424 unique genes and found that differentially expressed pleiotropic genes were significantly enriched in pancreas, liver, heart, and brain, and that the biological process of these genes was remarkably enriched in regulating neurodevelopment, neurogenesis, and neuron differentiation, offering substantial evidence supporting the validity of identified pleiotropic loci. We further demonstrated that among all the identified pleiotropic genes there were 342 unique ones linked with 6353 drugs with drug-gene interaction which can be classified into distinct types including inhibitor, agonist, blocker, antagonist, and modulator. We also revealed causal associations among psychiatric disorders, indicating that genetic overlap and causality commonly drove the observed co-existence of these disorders.ConclusionsOur study is among the first large-scale effort to characterize gene-level pleiotropy among a greatly expanded set of psychiatric disorders and provides important insight into shared genetic etiology underlying these disorders. The findings would inform psychiatric nosology, identify potential neurobiological mechanisms predisposing to specific clinical presentations, and pave the way to effective drug targets for clinical treatment.

Project description:BackgroundPreviously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes.MethodsTo explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity.ResultsOne consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior.ConclusionsOur findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.

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A summary-statistics-based approach to examine the role of serotonin transporter promoter tandem repeat polymorphism in psychiatric phenotypes.

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