Hormones & Sleep

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

Intronic regulatory polymorphism in the aromatase gene affecting CYP19A1 transcriptional activity via CEBPβ binding, with downstream effects on local estrogen synthesis, bone mineral density, and hormone-sensitive tissue biology

Missense variant in MTCH2 that reduces mitochondrial metabolic efficiency, increasing risk for obesity and sleep disruption through impaired energy substrate switching

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 across metabolic and oncological contexts

Melatonin receptor variant that extends nighttime melatonin signaling in pancreatic beta cells, impairing glucose-stimulated insulin secretion — especially when meals are eaten late

Missense variant in the inhibitory synapse regulator MDGA1 that impairs neuroligin-2/neurexin interaction, reducing GABAergic tone and increasing insomnia risk

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; the common C allele (Arg137, ~97.5% globally) has modestly reduced RGS16 function compared to the rare T allele (His137, ~2.5%), which is associated with morningness through enhanced cAMP gating in the master circadian clock

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 NUCB2 variant associated with obesity risk in males, type 2 diabetes risk in females, and colorectal cancer susceptibility — the T allele modestly affects nesfatin-1 signaling across multiple metabolic and oncological contexts

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

Rare protective missense variant in the NF-kB inhibitor zeta gene that reduces Th17-driven autoimmune thyroid inflammation and lowers hypothyroidism risk

Rare PER3 missense variant that destabilizes the circadian clock protein, shortening circadian period and causing familial advanced sleep phase syndrome 3 with associated seasonal mood vulnerability

Intronic CLOCK variant whose G allele, in a haplotype with rs4864548 A, confers a 1.8-fold increased risk of overweight and obesity and is associated with NAFLD, metabolic syndrome in shiftworkers, and altered food-timing patterns via disrupted circadian energy regulation

Tag SNP in the AGER 3′ downstream region associated with increased type 1 diabetes risk in HLA-predisposed individuals, implicating the AGE-RAGE inflammatory axis in autoimmune beta-cell susceptibility

Missense variant in pyridoxamine 5'-phosphate oxidase that reduces the enzyme's efficiency at converting dietary vitamin B6 into active PLP, the essential cofactor for GABA, serotonin, melatonin, and dopamine synthesis; associated with insomnia risk in large GWAS

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 in the AGER gene that increases RAGE transcription approximately threefold, raising both membrane-bound and soluble RAGE; the elevated RAGE expression amplifies AGE-driven inflammatory signaling and is associated with diabetic microvascular complications and coronary artery ectasia

Promoter variant at position -429 in the AGER gene that increases RAGE transcription, elevating membrane RAGE and altering soluble sRAGE levels; associated with higher inflammatory signaling through the AGE-RAGE-NF-κB axis and 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 — particularly in non-obese individuals — 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)

Affects TSH receptor sensitivity and thyroid hormone regulation; influences TSH levels, metabolic function, and congenital hypothyroidism risk

Intronic regulatory variant in ELK3 influencing circulating TSH levels and hypothyroidism susceptibility — the rare A allele increases risk by approximately 28% per copy

Regulatory variant near the HTR6 serotonin 6 receptor gene associated with chronotype; the minor T allele is linked to reduced morningness and a modest shift toward evening preference.

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

Core clock gene variant that shifts circadian period length and influences morning vs evening chronotype

Cryptochrome 1 circadian gene variant influencing glucose metabolism, sleep timing, mood regulation, and metabolic responses to diet

Missense variant in the GIP incretin hormone that changes its bioactivity and serum stability, with the derived Gly allele showing higher receptor activation and positive selection in Eurasian populations

Regulatory variant in a core clock gene that influences circadian timing, sleep-wake preference, and reward processing

Regulatory variant 2 kb upstream of PNPO that may alter expression of the vitamin B6-activating enzyme; the G allele shows the strongest single-SNP association with schizophrenia among PNPO variants in a Japanese population study, implicating impaired PLP production in psychiatric 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 under immune stress and acting as a severity modifier for complement-mediated inflammatory conditions and sleep disruption

Gain-of-function missense variant in the neuropeptide S receptor that increases receptor signaling ~10-fold, promoting wakefulness and reducing sleep duration

A missense variant in TYK2 that partially impairs JAK-family signaling downstream of IL-12, IL-23, and type I interferons, conferring broad protection against multiple autoimmune diseases including rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, type 1 diabetes, and hypothyroidism

Synonymous variant in CA14 near APH1A; T allele is associated with morning chronotype (OR=1.12) and tags regulatory variation at the gamma-secretase locus, linking circadian preference to APP cleavage biology and Alzheimer's sleep pathology risk

Synonymous coding variant in the VIP gene (Asn133Asn); the T allele may alter mRNA folding and VIP expression efficiency, with potential downstream effects on circadian SCN synchrony, neuroimmune modulation, and gut motility

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

Intronic variant in the orexin/hypocretin receptor 2 gene that tags the HCRTR2 chronotype locus; the C allele is associated with a modest shift toward morning preference

Regulatory variant 2 kb upstream of APH1A where the C allele (paper's G, coding strand) increases YY1 transcription factor binding and drives ~2.7-fold higher APH1A transcription, elevating gamma-secretase activity, increasing Aβ42 production, and raising Alzheimer's disease risk.

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 via iron homeostasis and dopaminergic dysregulation

Intergenic variant at 5p14.1 between neuronal cell-adhesion genes CDH9 and CDH10, associated with autism spectrum disorder risk and related social-communication and sleep phenotypes

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

Missense variant in C1-inhibitor gene associated with insomnia risk through neuroinflammatory and blood-brain barrier mechanisms

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

Missense variant reducing 5-alpha-reductase type 2 enzyme activity, affecting DHT production and response to finasteride

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

Synonymous variant in aromatase gene affecting estrogen production, bone density, and response to aromatase inhibitors

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

Missense variant in nucleobindin-2, the precursor protein cleaved to produce nesfatin-1 — a hypothalamic neuropeptide regulating appetite, energy homeostasis, blood pressure, and sleep-wake activity; the G allele is associated with protection against obesity and improved metabolic markers

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 and autoimmune thyroid disease

Intronic variant in the canonical restless legs syndrome gene BTBD9, associated with insomnia and RLS susceptibility via iron-dependent dopaminergic regulation in the brain

Intergenic variant ~54 kb downstream of the VIP gene; the C allele reduces VIP signaling capacity in the suprachiasmatic nucleus and is associated with evening preference and delayed sleep timing

Regulatory variant near FBXL3 that modulates circadian period length; the C allele is associated with an OR=1.19 for morningness chronotype in a 697,828-person GWAS

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