The Glucocorticoid Receptor Gene (NR3C1) 9β SNP Is Associated with Posttraumatic Stress Disorder

Abstract

Posttraumatic stress disorder (PTSD) has been associated with glucocorticoid (GC) hypersensitivity. Although genetic factors account for 30–46% of the variance in PTSD, no associations have been found between single nucleotide polymorphisms (SNPs) of the GC receptor (GR) gene (NR3C1) and risk for this disorder. We studied the association of five SNPs in the GR gene (rs10052957, rs6189/rs6190, rs6195, rs41423247, and rs6198) and haplotypes with PTSD, in a group of Portuguese male war veterans (33 with lifetime PTSD, 28 without). To determine whether the 9β SNP (rs6198) was associated with chronically altered cortisol levels, we evaluated hair cortisol concentrations (HCC) in a sample of 69 veterans’ offspring. The 9β variant (G allele) was significantly associated with lifetime PTSD under a dominant model of inheritance. The 9β variant was also significantly associated with severity of current PTSD symptoms. The haplotype analysis revealed an association between a common haplotype comprising the 9β risk allele and lifetime PTSD. Carriers of the 9β risk allele had significantly lower HCC than non-carriers. We found the 9β risk allele and a haplotype comprising the 9β risk allele of the GR gene to be associated with PTSD in veterans. This 9β risk allele was also associated with lower HCC in their offspring.

The assessment of combat exposure, mental and physical health problems in Portuguese colonial war veterans: A scoping review.

“…Overall, results indicated good to excellent internal consistency values for both subscales, ranging from .87 to .92 (Anxiety), and from .90 to .93 (Stress). No internal consistency values were reported in studies that used the HADS (Castro-Vale, Severo, & Carvalho, 2020), the SCL-90–R (Gamito et al, 2010), or the Structured Clinical Interview for DSM-IV axis I (Castro-Vale et al, 2019, 2021; Castro-Vale, Severo, & Carvalho, 2020; Castro-Vale, Severo, Carvalho, & Mota-Cardoso, 2020; Castro-Vale, van Rossum, et al, 2020).…”

The interplay between genetic variation and gene expression of the glucocorticoid receptor gene NR3C1 and blood cortisol levels on verbal memory and hippocampal volumes

“…In detail, SNP variation of rs56149945 was associated with verbal memory in both samples with the G-allele being associated with lower delayed memory performance. Although rs56149945 could be associated to various psychiatric disorders in the past [ 23 , 37 , 38 ] as well as cognitive features related to preterm birth [ 39 ], we are the first to report an effect on verbal memory of neutral words in the general population. The SNP itself is located in the first exon of the NR3C1 gene as a missense variant that causes an amino acid change from asparagine to serine or isoleucine ( https://www.ncbi.nlm.nih.gov/ , Fig.…”

“… We now aim to explore the association between the SNP rs56149945 of NR3C1 (also known as p.N363S or rs6195) on verbal memory in two independent samples from the general population. This genetic variant has been associated to HPA axis glucocorticoid sensitivity [ 22 ] as well as various stress induced psychiatric disorders [ 23 – 25 ]. Additionally, we intend to explore the role of the glucocorticoid cortisol on this path.…”

Emerging corticosteroid resistance: Need for customized medication based on pharmacogenomics profiling

“…The 9beta (rs6198) SNP, an adenine to guanine nucleotide substitution in the GR gene, is located in the GR9 region. The G allele of this polymorphism results in a more stable GR9 mRNA and increased GR9 isoform receptor protein synthesis, which may be related to GC resistance, according to in vitro findings (Castro-Vale et al, 2021). An ATTTA pattern symbolizes the shift from A to G in the nucleotide (to GTTTA).…”