Hormones & Sleep

Missense variant in circadian clock gene PER3 associated with morning chronotype preference and earlier diurnal timing

Intronic NUCB2 variant associated with type 2 diabetes risk in females and oral cancer progression in older males — the T allele modestly reduces nesfatin-1 signaling efficiency

Common variant in the 3' UTR of the DIO1 gene affecting thyroid hormone metabolism and T3/T4 ratio

Common leptin receptor variant in the leptin-binding domain affecting satiety signaling and metabolic regulation

Missense variant in RGS16 that substitutes histidine for arginine at position 137 of the G-protein signaling regulator expressed in the suprachiasmatic nucleus

T-cell receptor alpha locus variant associated with narcolepsy susceptibility, particularly in HLA-DQB1*06:02 positive individuals

3' UTR variant in RASD1 (Dexras1), a GTPase that gates light signals to the circadian clock in the suprachiasmatic nucleus; the G allele is associated with earlier chronotype (morningness)

Circadian clock gene variant affecting fasting glucose, hepatic lipid metabolism, and seasonal metabolic responses

Modulates local cortisol activation from cortisone in liver and adipose tissue, influencing visceral fat, insulin sensitivity, and metabolic syndrome risk

Intronic/regulatory variant near RGS16 that is the strongest single-locus morningness GWAS hit (P=7.0×10⁻¹⁸); the C allele (~4% global frequency) is associated with earlier chronotype via RGS16-mediated cAMP gating in the suprachiasmatic nucleus

Intronic variant in the brain-specific circadian transcription factor NPAS2; the T allele has been associated with prostate cancer susceptibility in a single candidate-gene study but lacks GWAS-level replication

Rare PER3 missense variant that co-occurs on the FASPS3 haplotype with Pro415Ala (rs150812083), further destabilizing the circadian clock protein and contributing to advanced sleep phase and seasonal mood vulnerability

Promoter region variant affecting sex hormone-binding globulin levels, with the A allele increasing SHBG by 15-25% and influencing free testosterone and estradiol bioavailability

Promoter variant at position -429 in the AGER gene linked to diabetic complications, cancer susceptibility, and sepsis risk

Core circadian clock transcription factor variant affecting mRNA stability, associated with evening preference, delayed sleep onset, and shorter sleep duration

Splice-site variant in the circadian clock gene CRY1 that causes exon 11 skipping, producing a gain-of-function protein that lengthens circadian period by ~30 minutes and drives Delayed Sleep Phase Disorder

Intronic variant tagging the HNF4A P2 promoter risk haplotype; the T allele impairs glucose-stimulated insulin secretion by reducing beta-cell-specific HNF4A isoform expression, and confers elevated diabetes risk with a notably strong effect under metabolic stress (OR 2.44 for post-transplant diabetes)

Intronic regulatory variant in ELK3 influencing circulating TSH levels and hypothyroidism susceptibility

Aryl hydrocarbon receptor variant in the transactivation domain that alters AHR signaling, affecting CYP1A2 inducibility, caffeine metabolism patterns, and circadian clock interactions

Missense variant in the AGER pattern-recognition receptor that reduces soluble RAGE shedding, amplifying inflammatory signaling via NF-κB and AGE pathway activation; associated with lung disease, diabetic complications, and modulated neuroinflammatory risk

Intronic HNF4A P2 promoter haplotype tag variant; carriers have modestly impaired glucose-stimulated insulin secretion and elevated type 2 diabetes susceptibility

Estrogen receptor alpha intron variant affecting receptor expression and estrogen sensitivity

Affects conversion of inactive T4 to active T3 thyroid hormone in brain, pituitary, and peripheral tissues

5' UTR variant in the APH1A gamma-secretase subunit gene, located 21 bp upstream of the translation start codon; studied alongside the -980C/G risk variant in sporadic Alzheimer's disease but not independently associated with disease risk

Missense variant (Pro10Leu) in melanopsin, the photopigment driving circadian photoentrainment; TT carriers show altered light-signaling amplitude and elevated seasonal affective disorder risk

5' UTR variant in C1-inhibitor gene that promotes partial exon 2 skipping, reducing C1-INH expression and acting as a severity modifier for complement-mediated inflammatory conditions

Synonymous variant in CA14 near APH1A; T allele is associated with morning chronotype (OR=1.12)

Missense variant in core circadian clock gene PER2 that lengthens intrinsic circadian period and shifts chronotype toward eveningness

Missense variant in the kynurenine pathway enzyme HAAO that shifts tryptophan flux toward quinolinic acid, a neurotoxic NMDA agonist, increasing insomnia risk

Second independent intronic BTBD9 variant associated with restless legs syndrome and periodic limb movements during sleep

Regulatory variant 54 kb upstream of the aryl hydrocarbon receptor gene; the strongest GWAS signal for habitual caffeine intake, influencing AHR expression, CYP1A2 inducibility, and caffeine clearance capacity

Final enzyme in melatonin synthesis; promoter variant reduces ASMT expression and lowers melatonin production, affecting sleep onset and circadian rhythm

Missense variant in glyoxalase 1 reducing enzyme activity, allowing methylglyoxal to accumulate — a GABA-A receptor modulator that influences anxiety and sleep quality

Promoter variant in the melatonin receptor 1B gene that alters MTNR1B expression, affecting circadian rhythm, morningness chronotype, and fasting glucose through impaired insulin secretion

Regulatory variant ~20 kb downstream of RGS16 that influences circadian chronotype; the C allele is associated with morningness preference (OR 1.21) in the largest replicated chronotype GWAS

Synonymous exon-10 variant that triggers alternative splicing of the G-protein beta-3 subunit, amplifying signaling through virtually every GPCR — affecting blood pressure, weight regulation, hormonal responses, sleep timing, and antidepressant efficacy

Upstream regulatory signal near the core circadian clock gene PER2 that shifts chronotype toward eveningness and increases susceptibility to shift-work misalignment

Adenosine A2A receptor variant that determines individual sensitivity to caffeine's effects on anxiety and sleep

Affects FSH receptor sensitivity, determining ovarian response to FSH stimulation and influencing fertility treatment dosing in both women and men

Intronic TSH quantitative trait locus in phosphodiesterase 8B — the G allele raises the thyroid set-point, increasing hypothyroidism risk and potentially affecting levothyroxine dose requirements

Promoter variant affecting 17α-hydroxylase expression and steroid hormone synthesis, influencing cortisol, DHEA, androgen, and estrogen production

Low-frequency intronic variant in FLT3 that creates a cryptic splice site, truncating the receptor in 30% of transcripts and doubling plasma FLT3 ligand per allele, substantially increasing risk of autoimmune thyroid disease (Hashimoto's) and other autoimmune conditions

Intronic variant in the PTCSC2 lncRNA that alters a FOXE1 enhancer element, modulating thyroid gland development and hypothyroidism risk

Low-frequency missense variant in adenylyl cyclase 7 that reduces cAMP synthesis by 40%, skews immune cells toward a pro-inflammatory Th2 phenotype, and is the strongest non-HLA coding risk factor for ulcerative colitis

Strongest GWAS thyroid locus — regulatory variant near FOXE1 affecting thyroid development, TSH levels, and differentiated thyroid cancer risk