rs1144566 — RGS16 RGS16 H137R

RGS16 H137R — A Coding Variant in the Circadian Clock's Synchronizer

Every cell in your body runs on a roughly 24-hour molecular clock, but those clocks need a conductor to stay synchronized with each other and with the outside world. That conductor lives in the suprachiasmatic nucleus (SCN)¹¹ suprachiasmatic nucleus (SCN)
A cluster of ~20,000 neurons in the hypothalamus directly above the optic chiasm; it receives light signals from the retina and broadcasts a 24-hour timing signal to every organ in the body via neural, hormonal, and temperature rhythms — and one of its critical molecular regulators is RGS16²² RGS16
Regulator of G-protein Signaling 16; a GTPase-accelerating protein that terminates Gαi/o signaling, thereby controlling when intracellular cAMP can accumulate in SCN neurons. The rs1144566 variant changes a single amino acid in RGS16 — histidine to arginine at position 137 — in a gene whose protein levels oscillate daily to gate the cAMP pulses that coordinate clock-neuron communication.

The Mechanism

RGS16 operates at a key node in the GPR176–Gz–RGS16 signaling axis³³ GPR176–Gz–RGS16 signaling axis
GPR176 is an orphan GPCR enriched in the SCN; it activates the Gz G-protein subunit (a slow-cycling member of the Gαi family), which suppresses cAMP synthesis; RGS16 terminates Gz signaling by accelerating GTP hydrolysis, releasing the cAMP brake. Each morning, the molecular clock drives a surge in RGS16 expression; this terminates the Gz-mediated cAMP suppression and allows cyclic AMP to accumulate — a biochemical event essential for synchronizing the phase-leading dorsomedial SCN neurons with the light-receiving ventrolateral neurons.

Doi et al. (2011)⁴⁴ Doi et al. (2011)
Doi M et al. Nature Communications, 2011 showed that mice lacking RGS16 entirely lose their circadian cAMP rhythm in the SCN and develop a lengthened free-running behavioral period. A longer internal period means the clock drifts toward an evening phase — the same directional shift associated with the C allele at rs1144566 in humans.

The H137R change (His→Arg at position 137) falls within the functional RGS domain responsible for G-protein contact. A positively charged arginine replacing a moderately polar histidine at this position is predicted to reduce GTPase acceleration of Gαi/o, impairing the protein's ability to terminate Gz signaling and thereby weakening the daily cAMP gate that sets circadian timing. This is a missense variant on a gene whose null phenotype directly produces the human evening-type circadian shift, making H137R a plausible partial loss-of-function that nudges carriers toward later timing.

The Evidence

The strongest human genetic evidence comes from two large independent GWAS that identified a chronotype signal at the RGS16 locus in high LD with rs1144566.

Hu et al. (2016)⁵⁵ Hu et al. (2016)
Hu Y et al. GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person. Nature Communications, 2016 found rs12736689 (in LD r²=0.89 with rs1144566) to be the single most significant chronotype hit genome-wide at P=7×10⁻¹⁸ in 89,283 participants, and explicitly noted that rs1144566 is the nearby nonsynonymous coding variant in high LD with the lead SNP. This positions H137R as the most compelling functional candidate underlying the association.

Jones et al. (2016)⁶⁶ Jones et al. (2016)
Jones SE et al. Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci. PLoS Genetics, 2016 independently confirmed the RGS16 locus in 128,266 UK Biobank participants, with the C-allele at the linked rs516134 conferring an odds ratio of 1.21 (95% CI 1.15–1.27) for morningness at P=3×10⁻¹². The RGS16 locus is the most replicated single locus in human chronotype genetics, confirmed in at least three independent GWAS totaling over 700,000 individuals.

The mechanistic grounding was extended by Nakagawa et al. (2020)⁷⁷ Nakagawa et al. (2020)
Nakagawa S et al. Time-Restricted G-Protein Signaling Pathways via GPR176, Gz, and RGS16 Set the Pace of the Master Circadian Clock in the SCN. IJMS, 2020, which showed that RGS16 protein peaks in the early morning in SCN neurons and that this timed expression is indispensable for the cAMP surge that coordinates cellular synchrony. Human genetic variants of RGS16 associating with earlier wake-up times are highlighted as the translational implication of these rodent findings.

The evidence level is rated moderate rather than strong because the functional impact of H137R specifically has not been characterized in cell or animal models — the GWAS signal is well-established, but whether H137R is the causal variant (versus being a proxy for a linked regulatory variant like rs516134) has not been definitively resolved.

Practical Implications

The C allele (H137R / Arg137) is the overwhelmingly common allele globally (~97.5%), making the CC genotype the population default. The H137R form of RGS16 has modestly reduced GTPase activity compared to the ancestral His137 form, but since nearly everyone carries it, this represents the baseline circadian setting rather than a deviation from normal.

The rare T allele (~2.5% globally) encodes the ancestral His137 form with stronger GTPase activity. Carriers of the T allele (CT or TT genotypes, ~5% of people) have a circadian clock that may run with slightly tighter phase advance — the practical expression is a modest morning preference with easier early waking. The T allele is most common in European (~2.5%) and African (~5.5%) ancestry populations and rarest in East Asian populations (~0.1%).

Interactions

rs1144566 sits at the same RGS16 locus as the regulatory variant rs516134 and the linked rs12736689. Both the coding change (rs1144566) and the regulatory signal (rs516134/rs12736689) independently tag the circadian effect at this locus, and they are in high LD (r²=0.89), so most users with the rs1144566 T allele will also carry the morningness-associated allele at rs12736689.

For additive circadian effects, variants in CLOCK (rs1801260) and PER3 (rs5751876) act at different nodes of the same oscillator. Carriers of morningness alleles at both RGS16 (T) and CLOCK may experience stronger morning preference than either variant alone predicts, as the two genes affect different parts of the feedback loop — RGS16 affects intercellular cAMP synchrony while CLOCK affects transcription-factor stability in the core loop.