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

Arunabha Majumdar,Roel A Ophoff,Bogdan Pasaniuc,Preksha Patel

doi:10.1038/s41431-021-00996-6

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.

Highlights

Large-scale human genetic studies have resulted in major breakthroughs for our understanding of the genetic architecture of complex human traits
We successfully developed and applied a genome-wide association studies (GWAS) summarystatistics-based approach to examine the direct effect of the serotonin transporter (SLC6A4) promoter variable number of tandem repeat (VNTR) polymorphism (5HTTLPR) on susceptibility of neurobehavioral traits and psychiatric disorders in the largest available samples for genetic studies
Table 4. 5-HTTLPR association p values obtained by VNTR.s for the first set of psychiatric phenotypes in GWAS atlas

Summary

INTRODUCTION

Large-scale human genetic studies have resulted in major breakthroughs for our understanding of the genetic architecture of complex human traits. The genetic association signal findings between 5-HTTLPR and psychiatric and neurobehavioral phenotypes have been found to be inconsistent across studies, few indicating an association, for example, when interacting with stressful life events [7], but a meta-analysis with a total sample size of more than 14,000 participants failed to provide any evidence for association with depression with or without stressful life events [8]. In order to revisit the 5-HTTLPR for genetic analysis in the largest study samples available, we developed and applied a GWAS summarystatistics-based approach for association testing of this locus. If the 5-HTTLPR genotypes are missing in a different dataset, but the genotypes of the eight tag SNPs are available, we can use Gb 1⁄4 bγx to predict the 5-HTTLPR genotypes, where x is the genotype vector for the tag SNPs. genetic polymorphisms in disease risk and trait susceptibility of phenotypes for which summary-level data from large-scale GWAS are available. We assume that the individual-level data for Y and genotypes

METHODS

Majumdar et al 4

DISCUSSION

ETHICAL APPROVAL