Neurology & Cognition

Intergenic regulatory variant ~26 kb downstream of CALCB (calcitonin gene-related peptide beta) that is the first GWAS locus to directly implicate the CGRP-encoding gene region in migraine susceptibility; the minor A allele increases migraine risk and the variant is a cis-eQTL for CALCB — the direct molecular target of anti-CGRP monoclonal antibodies and gepants

Intronic variant in the AMPA glutamate receptor gene GRIA1 associated with restless legs syndrome risk via hyperglutamatergic thalamic excitability

Intronic CD58 variant with a dual role — the G allele increases T-cell activity and NMO susceptibility by facilitating AQP4-antibody CNS entry, while the TT genotype reduces CD58 surface expression and suppresses regulatory T cells, conferring autoimmune thyroid disease risk

Upstream regulatory variant of the cold-sensing TRPM8 channel that modulates migraine susceptibility, cold pain sensitivity, and brown adipose thermogenesis

Promoter variant in the GRIN2B Sp1 binding site that reduces NR2B subunit expression, lowering NMDA receptor activity critical for learning and memory

Common intronic variant in CACNA1A — the P/Q-type calcium channel gene mutated in familial hemiplegic migraine — that reaches genome-wide significance for migraine with aura; the G (reference) allele confers typical susceptibility while the A allele is mildly protective

Intronic variant near KCNK5 that reduces TASK2 potassium channel expression and increases migraine susceptibility; the T allele is associated with lower KCNK5 expression and an ~5% elevated odds of migraine per allele in the largest GWAS to date.

Stop-gain mutation eliminating connexin 26 function; the most common GJB2 deafness allele in South Asian populations and the ancestral founder mutation carried into European Romani communities

Intergenic variant downstream of TSHZ1, a transcription factor essential for inner ear and auditory canal development; the A allele is associated with increased constitutional susceptibility to motion sickness via vestibular pathway architecture

3' UTR variant in the neurocan gene associated with bipolar disorder and schizophrenia risk, with measurable effects on hippocampal memory function and limbic brain structure

Intronic variant near the cholecystokinin B receptor gene associated with restless legs syndrome risk through dopaminergic signaling in the basal ganglia

Intronic variant in the AMPA glutamate receptor gene GRIA4 associated with restless legs syndrome risk via hyperglutamatergic thalamic excitability

Intronic variant in clusterin gene affecting Alzheimer's disease risk through regulation of amyloid-beta clearance

Rare splice donor variant in ABCA7 that disrupts mRNA processing, causing haploinsufficiency of a key amyloid-clearance lipid transporter; one of the strongest non-APOE genetic risk factors for late-onset Alzheimer's disease

Intronic variant in neuroligin 1, a postsynaptic cell adhesion molecule essential for excitatory synapse formation and NMDA-dependent plasticity; the C allele increases susceptibility to motion sickness and impairs habituation to repeated motion exposure at genome-wide significance (P=5.9×10⁻¹³)

Intronic variant in the INPP5F/BAG3 locus associated with increased risk of REM sleep behavior disorder — an early marker of Lewy body neurodegeneration

Missense variant in EVI5's coiled-coil domain altering immune cell trafficking and multiple sclerosis susceptibility

SNCA 3′-region variant in the extended 3′ UTR that affects alpha-synuclein mRNA stability and expression, consistently associated with Parkinson's disease risk across Asian and European populations

Intronic CD58 variant in strong LD with rs2300747 (r²=0.929); the C allele drives MS susceptibility (OR 2.22 for CC) and predicts poor IFN-beta therapy response — the pharmacogenomic dimension absent from its LD partner

Intronic variant in IL1RAP that impairs microglial activation, accelerating brain amyloid accumulation and Alzheimer's disease progression independently of APOE status

Coding variant in CD33 (Siglec-3) that alters exon 2 splicing in microglia — the T allele promotes exon 2 skipping, producing a short CD33 isoform that lacks the sialic acid-binding IgV domain and enhances microglial phagocytosis of amyloid-beta, reducing Alzheimer's disease risk

Intronic variant near heme oxygenase 2 (HMOX2) associated with migraine-with-aura susceptibility; the G allele (GRCh38 reference) tags a regulatory effect on constitutive CO production in cerebral vessels, modulating cerebrovascular reactivity relevant to aura pathophysiology

Regulatory variant upstream of ferroportin (the sole cellular iron exporter) linked to restless legs syndrome through impaired brain iron delivery

Intronic GBA variant associated with REM sleep behavior disorder via lysosomal autophagy impairment; the T allele confers OR=2.09 for RBD in the largest GWAS of this condition to date

Intronic CD58 variant that sits inside the miR-548ac stem-loop; the A allele disrupts Drosha cleavage, simultaneously lowering CD58 mRNA and raising miR-548ac levels — the functional mechanism underlying the CD58 locus MS association

Pathogenic missense variant at the TMPRSS3 autocatalytic cleavage site causing serine protease domain dysfunction and autosomal recessive sensorineural hearing loss (DFNB8/DFNB10); originally identified in consanguineous Turkish families

Intronic CD58 variant hosting the miR-548ac stem-loop; the C allele creates a G-U wobble base pair that enhances Drosha cleavage, increasing miR-548ac while reducing CD58 mRNA — the mechanistic anchor of the CD58 MS-risk haplotype

Rare missense variant in the lysosomal exonuclease PLD3 that impairs endolysosomal function and amyloid precursor protein processing, associated with approximately doubled late-onset Alzheimer's disease risk in the discovery cohort (OR ~2.10) and a pooled OR of 1.53 in meta-analysis; replication has been inconsistent across large European cohorts.

Intronic regulatory variant in CLU (clusterin/apolipoprotein J) that controls neuronal clusterin expression; the protective T allele elevates CLU transcription, enhancing amyloid-beta clearance across the blood-brain barrier and reducing Alzheimer's disease risk

Intronic variant in TOMM40 (translocase of outer mitochondrial membrane 40) associated with aging-related verbal memory decline, accelerated hippocampal atrophy, and Alzheimer's disease risk, with effects partially independent of APOE

Influences episodic memory performance and hippocampal function through the KIBRA protein's role in synaptic plasticity

Gain-of-function variant in the P2X7 receptor that increases ATP-gated pore formation, IL-1β release, and microglial neuroinflammation, associated with mood disorders and chronic pain severity

Intronic CADM2 variant genome-wide significant for information processing speed; the C allele is associated with slower reaction time and cognitive throughput, while T carriers show faster symbol-digit substitution performance

Haplotype-tagging variant distinguishing MAPT H1 and H2 clades, affecting risk for Parkinson disease, progressive supranuclear palsy, and other tauopathies

Intronic MAPT variant that directly regulates tau exon 3 splicing via differential hnRNP F/Q binding; the G allele (H1 haplotype) reduces exon 3 inclusion, elevating 4-repeat tau isoforms and increasing risk for Parkinson's disease, PSP, and corticobasal degeneration

Intronic variant in the sortilin-related receptor that tags a 3′ haplotype block linked to reduced SORL1 brain expression; the A allele is associated with lower receptor levels and modestly increased Alzheimer's disease risk

Missense variant (Met270Thr) in RNF213, the major moyamoya disease susceptibility gene; the C allele reached genome-wide significance for migraine risk (OR=1.06), linking vascular remodeling genetics to common headache disorders

Intronic MAPT variant that regulates tau exon 3 splicing via hnRNP F/Q binding, distinguishing H1 (risk) from H2 (protective) haplotypes for Parkinson's disease, PSP, corticobasal degeneration, and Alzheimer's disease

Splice-region variant in TNFR1 that generates a soluble Δ6 isoform mimicking anti-TNF drugs, conferring MS risk and explaining why TNF blockers worsen demyelinating disease

Hypomorphic missense variant in the TMPRSS3 serine protease catalytic domain; the most common TMPRSS3 pathogenic allele worldwide, causing DFNB8 progressive or DFNB10 congenital hearing loss depending on the second allele; a founder mutation in Korean, Chinese, Dutch, and German populations

Regulatory variant at chromosome 6q16.1 near POU3F2 (BRN2), a master transcription factor for cortical neuron development; the A allele is associated with higher general cognitive ability and educational attainment in GWAS studies totalling over 1 million individuals

Recessive pathogenic APP missense variant causing early-onset Alzheimer's disease in homozygotes; heterozygous carriers are unaffected due to a dominant-negative inhibition of amyloid aggregation

Regulatory variant in the TSPAN2/NGF locus on chromosome 1p13; the C allele is one of the largest-effect migraine risk variants identified in the genome, with particular elevation of risk for migraine without aura through a peripheral trigeminal sensitization mechanism driven by nerve growth factor signalling

Gain-of-function missense variant in the P2X7 ATP-gated receptor that increases receptor expression and ion channel activity, heightening neuroinflammation and linked to mood disorders, pain sensitization, and infection severity

Regulatory variant near MUTED/BLOC1S5, a gene whose mouse homolog controls otolith synthesis in the vestibular labyrinth; the G allele increases susceptibility to motion sickness at genome-wide significance

Missense variant in the C-terminal domain of the P2X7 receptor that disrupts normal receptor dimerisation when coexpressed with the wild-type allele, with the G (Arg460) allele associated with major depressive disorder in a large meta-analysis and with higher multiple sclerosis severity scores; the A (Gln460, low-activity) allele is independently linked to rapid cycling in bipolar disorder

Intronic variant in MEF2D encoding a key neuronal transcription factor that regulates excitatory synapse development and neuronal survival; the C allele is associated with increased migraine susceptibility in the largest migraine GWAS to date (OR=1.075, P=3.0E-41, 102,084 cases) and is thought to subtly alter MEF2D expression in cortical and trigeminal neurons, modulating synaptic excitability thresholds

Intronic variant in CD58 (LFA-3) that modulates T-cell costimulation and Treg function; the protective G allele raises CD58 expression and reduces multiple sclerosis risk

Intronic variant in the alpha-T-catenin gene associated with modestly increased late-onset Alzheimer's disease risk, with the strongest female-specific signal in intron 9 of CTNNA3

Intronic MAPT variant tagging the H1c sub-haplotype within the H1 clade, independently elevating risk for progressive supranuclear palsy and corticobasal degeneration through increased 4-repeat tau expression

Intronic MAPT variant whose T allele co-defines the H1c sub-haplotype, independently conferring OR 1.85 for progressive supranuclear palsy and OR 2.07 for corticobasal degeneration in the same meta-analysis validating rs242557

Regulatory variant in the 5' UTR of DDX39B (RNA helicase/mRNA export factor) that reduces DDX39B translation, impairing IL7R exon 6 inclusion and increasing soluble IL7R — the strongest known epistatic interaction in MS genetics

SNCA upstream regulatory variant (near gene-5) that is part of the 4-SNP SNCA risk haplotype (OR 2.51 for PD) and shows an independent TT homozygote association with Parkinson's disease risk and cognitive impairment

Missense variant at position 308 of the orexin receptor 2 protein; the minor Ile308 allele (A) reduces receptor activity, increasing daytime napping tendency and evening chronotype, while placing the variant directly at a drug target for orexin antagonist sleep medications

Intronic SNCA variant (intron 4) associated with Parkinson's disease risk and cognitive impairment; the G allele upregulates alpha-synuclein protein levels and is independent of rs356219

Intronic variant in PTK2 (focal adhesion kinase) linked to restless legs syndrome through disrupted neuronal circuit development and sensory-motor signaling

Tag SNP for HLA-DRB5*01:01 on the DR15 susceptibility haplotype, physically near HLA-DRB5 in the MHC region and in near-complete LD with rs3135388; the DRB5*01:01 allele contributes independently to multiple sclerosis and narcolepsy risk by presenting myelin and viral peptides to autoreactive CD4+ T cells

Tag SNP for HLA-DRB1*15:01 (physically located near HLA-DRA), the strongest genetic risk factor for multiple sclerosis, with implications for vitamin D optimization and EBV immune control

Exon 8 missense variant in the IL-7 receptor alpha chain (Ile356Val) associated with modestly increased multiple sclerosis susceptibility under a recessive model; unlike rs6897932, no functional splicing or expression mechanism has been established

Lysosomal K+/H+ channel variant (p.Met393Thr) that impairs lysosomal pH regulation, slows alpha-synuclein clearance, and increases risk for Parkinson's disease and REM sleep behavior disorder

Parkinson's disease GWAS risk variant affecting alpha-synuclein expression and neuronal differentiation

SNCA 3′-region regulatory variant that upregulates alpha-synuclein expression and independently increases Parkinson's disease risk, earlier onset, and cognitive decline

Connexin 26 missense variant causing partial loss of cochlear gap junction function; the main mild-severity GJB2 deafness allele in European populations, with reduced penetrance and typically mild-to-moderate hearing loss

Loss-of-function variant in the P2X7 receptor that reduces inflammatory response and may modulate pain sensitivity

Intronic SNCA variant at the 5′ locus associated with REM sleep behavior disorder risk — the strongest genetic prodromal marker for Lewy body neurodegeneration

Intronic MAPT variant whose A allele defines the H1h sub-haplotype — a configuration distinct from H1c — independently associated with non-tremor dominant Parkinson's disease at OR 2.9 after Bonferroni correction, and sharing no meaningful linkage disequilibrium with the H1c-defining markers rs242557 or rs2471738 (r² ≈ 0.01)

Variant in the PICALM gene affecting amyloid-beta clearance across the blood-brain barrier and Alzheimer's disease risk

Promoter-region variant that modulates CD33 expression on microglia — the protective A allele reduces surface CD33, enhancing microglial clearance of amyloid-beta and conferring modest protection against late-onset Alzheimer's disease

Missense variant in TNF receptor 1 that causes low-penetrance TRAPS (recurrent fever syndrome) and independently raises multiple sclerosis risk ~1.6-fold via stronger TNF binding and altered receptor trafficking

Regulatory 5'UTR variant in the dopamine D1 receptor gene influencing receptor density and cognitive efficiency under high cognitive load

Near-gene variant tagging the TMPRSS3 hearing loss locus on chromosome 21, associated with susceptibility to sensorineural hearing loss and carrier status for DFNB8/10 deafness

Intronic variant in the super elongation complex gene AFF3; the T allele increases AFF3 expression and was one of three original genome-wide significant hits for educational attainment (Rietveld 2013), with replication in all subsequent large GWAS

Intronic variant in GPD2 (mitochondrial glycerol-3-phosphate dehydrogenase), second-strongest signal (P=1.5×10⁻²⁹) from the first-ever motion sickness GWAS; the G allele is in high LD with a missense variant that alters GPD2 enzyme activity and is linked to impaired glucose homeostasis during vestibular stress

Missense variant in CACNA1H encoding the CaV3.2 T-type calcium channel; the Leu640 allele has population-level associations with migraine risk and alters channel pharmacodynamics, set against a backdrop of CaV3.2's established role in hippocampal memory consolidation and synaptic plasticity.

Intronic PRDM16 variant reaching genome-wide significance in the first motion sickness GWAS, with the same risk allele independently associated with antimigraine medication use — pointing to a shared genetic basis for vestibular vulnerability and migraine susceptibility

Missense mutation replacing asparagine with tyrosine at position 141 of presenilin-2, causing early-onset autosomal dominant Alzheimer's disease in a Chinese Han family; absent from gnomAD and classified pathogenic by ACMG criteria

Key neurotrophin variant that controls activity-dependent BDNF release, affecting memory consolidation, neuroplasticity, and stress resilience

Pathogenic missense variant in PSEN2 (presenilin-2) causing autosomal dominant familial Alzheimer's disease with variable onset (44–68 years) and documented incomplete penetrance; shifts gamma-secretase cleavage toward longer, aggregation-prone Aβ42 peptides

Pathogenic PSEN1 missense mutation (His163Tyr) that impairs gamma-secretase processivity, elevating the Aβ42/Aβ40 ratio and causing autosomal dominant early-onset familial Alzheimer's disease with average onset around age 51.

Pathogenic PSEN1 missense variant at codon 278 that disrupts gamma-secretase substrate processing, shifts amyloid-beta production toward longer amyloidogenic species (Aβ42, Aβ43), and causes autosomal dominant early-onset familial Alzheimer's disease typically presenting between ages 40 and 55.

Rare pathogenic PSEN1 missense variant substituting leucine for phenylalanine at position 177 in the gamma-secretase catalytic subunit; elevates Aβ42/Aβ40 ratio with relatively preserved total cleavage activity, classified as pathogenic for early-onset familial Alzheimer's disease

Rare pathogenic missense variant in APP at the gamma-secretase cleavage site causing familial early-onset Alzheimer's disease with cerebral amyloid angiopathy; the "Calabrian" founder mutation originating in southern Italy over 1,000 years ago

Rare pathogenic missense variant in APP near the gamma-secretase cleavage site causing autosomal dominant early-onset familial Alzheimer's disease; the "Australian" mutation first identified in an early-onset kindred, increasing amyloid-beta42/43 production 1.4- to 1.9-fold

Pathogenic missense mutation in PSEN1 (presenilin-1) causing autosomal dominant familial early-onset Alzheimer's disease with exceptionally early symptom onset, typically in the mid-to-late twenties

Synonymous variant in BACE1 (beta-secretase 1) linked to modestly elevated Alzheimer's disease risk, particularly in APOE4 carriers; may affect mRNA processing or expression rather than protein sequence.

Intronic variant in the calsyntenin-2 gene associated with episodic memory performance and hippocampal inhibitory circuit function

Intronic variant in the complement receptor 1 gene; the minor A allele impairs complement-mediated clearance of amyloid-beta and increases late-onset Alzheimer's disease risk with an odds ratio of ~1.21

Intergenic variant ~1.1 Mb upstream of NECTIN3/PVRL3; the strongest genome-wide signal for motion sickness susceptibility (P=4.2×10⁻⁴⁴ in 80,494 individuals), attributed to the PVRL3 locus whose encoded cell adhesion protein is required for normal ocular development and visual sensory input to the brain

Intronic variant in FHL5 (four and a half LIM domains 5), a transcriptional coactivator regulating cAMP-responsive gene programs in vascular smooth muscle cells; the T allele increases migraine susceptibility with an odds ratio of 1.09 per allele, identified across multiple large GWAS totaling over 160,000 cases

Common variant in the Nav1.7 sodium channel affecting pain sensitivity and pain threshold

Intronic variant affecting thermal pain sensitivity and central pain signal transmission

Intergenic variant at the HTR1F locus on chromosome 3; the minor A allele increases migraine susceptibility at genome-wide significance and sits within the genomic region encoding the 5-HT1F serotonin receptor — the direct drug target of lasmiditan (Reyvow), the first ditan-class migraine treatment

Intergenic variant near ARAP2 associated with motion sickness susceptibility at genome-wide significance; one of only three loci from the first motion sickness GWAS to also associate with postoperative nausea and vomiting, making it clinically relevant for pre-surgical risk assessment

Splicing variant in the IL-7 receptor alpha chain that shifts the balance toward soluble receptor, amplifying IL-7 signaling and raising susceptibility to multiple sclerosis and related autoimmune conditions

Intronic variant in GAB2 that modulates late-onset Alzheimer's disease risk; the minor G allele is protective, associated with higher GAB2 expression and reduced tau and amyloid pathology in brain tissue

Connexin 26 missense variant causing partial loss of cochlear gap junction function; the leading cause of mild-to-moderate hereditary hearing loss in East Asian populations

Frameshift deletion in TMPRSS3 causing premature stop at codon 88; a severe pathogenic allele and Slovenian founder mutation causing DFNB8/10 autosomal recessive sensorineural hearing loss

Second strongest genetic risk factor for Alzheimer's disease after APOE, associated with increased tau pathology and accelerated cognitive decline

Rare missense variant in microglial receptor TREM2 that significantly increases late-onset Alzheimer's disease risk through impaired microglial function and amyloid clearance

GBA missense variant (p.Asn409Ser, formerly N370S) — the most common GBA pathogenic allele; heterozygotes carry substantially elevated risk for Parkinson's disease, Lewy body dementia, and REM sleep behavior disorder; homozygotes develop Gaucher disease type I

Common noncoding variant upstream of LRRK2 that increases gene expression in microglia and Parkinson's disease risk

Intronic SCARB2 variant associated with REM sleep behavior disorder risk via the lysosomal GBA-trafficking pathway — the molecular bridge between glucocerebrosidase delivery and alpha-synuclein clearance

Intronic ABCA7 variant tagging an expanded VNTR that disrupts amyloid-beta clearance by microglia and impairs neuronal phosphatidylcholine metabolism, increasing Alzheimer's disease risk approximately twofold

P2RX7 variant with a unique dual mechanism — gain-of-function in channel opening and loss-of-function in pore formation — associated with chronic pain susceptibility, neuroinflammation, and modulation of microglial signaling

Promoter variant affecting GTP cyclohydrolase 1 expression and pain sensitivity, with opposite effects in European vs African populations

The most common cause of autosomal recessive nonsyndromic hearing loss in Europeans; homozygous deletion eliminates connexin 26 function and causes severe-to-profound congenital deafness

The most common GJB2 deafness allele in the Ashkenazi Jewish population (~4% carrier frequency); frameshift deletion eliminates connexin 26 function and causes congenital sensorineural hearing loss in homozygotes or compound heterozygotes

Frameshift deletion eliminating connexin 26 function; the most common GJB2 deafness allele in East Asian populations causing severe-to-profound prelingual sensorineural hearing loss

Capsaicin receptor variant affecting heat and pain sensitivity

Intergenic eQTL near HLA-DQA1 that tags the DR15 haplotype (DRB1*15:01/DQA1*01:02/DQB1*06:02), the strongest genetic risk factor for multiple sclerosis, and is also associated with SLE and ulcerative colitis

Intergenic SNP between HLA-DQB1 and HLA-DQA2 that tags the DQB1*06:02 allele, the third component of the DR15 haplotype (DRB1*15:01/DQA1*01:02/DQB1*06:02), conferring risk for multiple sclerosis, SLE, and narcolepsy; the T allele is protective

Intergenic regulatory variant upstream of POU3F2 (BRN-2), a transcription factor critical for cortical neuron differentiation; the A allele (risk) is the most-replicated genome-wide significant hit for educational attainment, associated with approximately 1 month less schooling per allele via altered POU3F2 expression in fetal and adult brain

Intronic regulatory variant in PHACTR1 that controls endothelin-1 and arterial compliance; the A allele is one of the strongest migraine GWAS hits (OR ~1.08, P=1×10⁻⁴⁷) while the G allele shows the opposite pattern — protective against migraine but a major coronary artery disease risk factor, demonstrating striking pleiotropy across five vascular diseases