rs11954376 (HTR1A): CRP and Inflammation Variant

Key takeaways

• A genome-wide study found rs11954376, located near HTR1A (the gene encoding the serotonin 1A receptor, a protein involved in brain and nervous system signaling), among hundreds of genetic signals associated with C-reactive protein (CRP), a blood marker of systemic inflammation.
• It was one of 797 independent signals across 283 genetic loci reaching genome-wide significance (p < 5 x 10^-8) in a multi-trait analysis of CRP and cardiometabolic traits.
• The study identified shared genetic pathways between CRP and traits including HDL and LDL cholesterol, triglycerides, BMI, and smoking behavior.
• No variant-specific effect size for rs11954376 is available in the current evidence base.
• Evidence comes from a single study with no reported independent replication for this specific locus.

What the research says Koskeridis et al. (Nature Communications, 2022) performed Multi-Trait Analysis of GWAS (MTAG, a statistical method that jointly analyzes multiple genetically correlated traits to increase detection power) on CRP levels combined with HDL cholesterol, LDL cholesterol, triglycerides, body mass index (BMI), and cigarettes per day, identifying rs11954376 as one of 797 genome-wide significant signals in 283 genetic loci. The study identified 41 novel loci overall and noted that 12 variants displayed discordant effects between CRP and the co-analyzed cardiometabolic traits, meaning a single variant associated with two traits in opposite directions. The annotation of this locus to the serotonin 1A receptor region is notable because this gene is primarily studied in neuropsychiatric contexts, though the available study text does not elaborate on a mechanistic link between this region and CRP biology.

Reported associations

• C-reactive protein (CRP) levels: rs11954376 is one of 797 genome-wide significant signals identified through MTAG analysis of CRP and five cardiometabolic traits; no variant-specific effect size is reported in the available study text.
• Cardiometabolic traits (pleiotropic context): The MTAG framework assessed genetic overlap across HDL cholesterol, LDL cholesterol, triglycerides, BMI, and cigarettes per day alongside CRP; whether rs11954376 specifically co-associates with any of these secondary traits is not described in the available excerpt.

Evidence quality The signal for this locus was detected through MTAG, which leverages correlations across traits to increase statistical power and can surface loci that would not reach significance in single-trait GWAS. Across the full multi-trait analysis, 797 signals in 283 loci reached genome-wide significance (p < 5 x 10^-8), but no sample size, variant-specific p-value, odds ratio, or beta coefficient is reported for this locus in the available text. No independent replication cohort is described for this specific signal. The annotation of this region to HTR1A raises the possibility of a pleiotropic connection between inflammation biology and neural receptor function, but the available evidence does not establish or explore that mechanism for rs11954376 specifically. This evidence should be treated as preliminary.

Lifestyle considerations No lifestyle considerations on file for this variant.