Abstract
Genetic variants of ESR1 have been implicated in multiple diseases, including behavioral disorders, but causative variants remain uncertain. We have searched for regulatory variants affecting ESR1 expression in human brain, measuring allelic ESR1 mRNA expression in human brain tissues with marker SNPs in exon4 representing ESR1-008 (or ESRα-36), and in the 3’UTR of ESR1-203, two main ESR1 isoforms in brain. In prefrontal cortex from subjects with bipolar disorder, schizophrenia, and controls (n = 35 each; Stanley Foundation brain bank), allelic ESR1 mRNA ratios deviated from unity up to tenfold at the exon4 marker SNP, with large allelic ratios observed primarily in bipolar and schizophrenic subjects. SNP scanning and targeted sequencing identified rs2144025, associated with large allelic mRNA ratios (p = 1.6E10-6). Moreover, rs2144025 was significantly associated with ESR1 mRNA levels in the Brain eQTL Almanac and in brain regions in the Genotype-Tissue Expression project. In four GWAS cohorts, rs2104425 was significantly associated with behavioral traits, including: hypomanic episodes in female bipolar disorder subjects (GAIN bipolar disorder study; p = 0.0004), comorbid psychological symptoms in both males and females with attention deficit hyperactivity disorder (GAIN ADHD, p = 0.00002), psychological diagnoses in female children (eMERGE study of childhood health, subject age ≥9, p = 0.0009), and traits in schizophrenia (e.g., grandiose delusions, GAIN schizophrenia, p = 0.0004). The first common ESR1 variant (MAF 12–33% across races) linked to regulatory functions, rs2144025 appears conditionally to affect ESR1 mRNA expression in the brain and modulate traits in behavioral disorders.
Highlights
The estrogen signaling pathway plays a pervasive role throughout the body
Since many of the SNPs with significant associations are not in high Linkage disequilibrium (LD) with each other, these results suggest a complex landscape of functionally relevant polymorphisms, while the causative variants have remained elusive
Linkage disequilibrium (LD) between each variant analyzed is provided in Table C in S1 File, showing that the selected SNPs cover several haplotype blocks in ESR1.Use of all significant allelic expression imbalance (AEI) ratio (>1.37–1.38) failed to reveal strong associations with any candidateSNP; we focused on large AEI ratios >2, observed only in the bipolar and schizophrenic subjects with rs1801132 exon4 marker
Summary
The estrogen signaling pathway plays a pervasive role throughout the body. Significant evidence supports a role in neuropsychiatric disorders, modulating positive symptoms of schizophrenia, mania in bipolar individuals, and cognition and emotion as a result of hormonal fluctuations [1]. Most studies on ESR1 have focused on effects observed in females; some estrogen receptor isoforms appear to signal in a ligand-independent fashion [2, 3] and estrogens are generated in the brains of females and males. Signaling via estrogen receptor alpha (ESR1) is critical in females and in males [4]; yet, few studies on ESR1 have focused on males, mostly with inconclusive results [5, 6]. We focus here on ESR1 variants affecting behavioral traits in neuropsychiatric disorders, including bipolar disorder, ADHD, and schizophrenia [12]
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