rs2568958 — NEGR1 NEGR1 depression/BMI variant

NEGR1 and the Mood-Weight Connection — When Your Brain's Wiring Governs Both

Most genetic risk factors influence one thing. NEGR1¹¹ NEGR1
Neuronal Growth Regulator 1 — a GPI-anchored cell adhesion molecule in the IgLON superfamily, expressed on the surface of neurons in the hypothalamus, hippocampus, and prefrontal cortex. GPI-anchored means the protein is tethered to the outer cell membrane by a lipid anchor rather than spanning it — placing NEGR1 at the neuron's outermost face where it mediates cell-to-cell contact influences two. Variants near this gene are among the most replicated findings in both the obesity and the major depression genetics literature — the same neurons that control appetite circuits in the hypothalamus also organize the monoaminergic signaling that underlies mood regulation.

Rs2568958 sits near a 45-kilobase deletion polymorphism upstream of NEGR1 that was first identified in 2009 as one of six new BMI loci²² six new BMI loci
Willer CJ et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet, 2009 reaching genome-wide significance, and has since been independently confirmed in the depression GWAS literature as part of the same causal signal.

The Mechanism

NEGR1 belongs to the IgLON superfamily³³ IgLON superfamily
A family of immunoglobulin-domain cell adhesion molecules — LSAMP, OPCML, NRCAM, NEGR1, and HNT/NTROPHY — that guide axonal growth and synapse formation. They are expressed on the outer surface of neurons and regulate which neurons bond with which, effectively controlling the wiring diagram of the developing and adult brain. In the hypothalamus, NEGR1 guides the physical architecture of circuits that integrate energy status signals with behavioral outputs — it helps wire the neurons that receive leptin and insulin signals and translate them into satiety, mood, and energy expenditure.

The rs2568958 G allele disrupts NEGR1 expression through two mechanisms. First, it lies near a structural deletion⁴⁴ structural deletion
The Willer 2009 study identified a 45-kb deletion immediately upstream of NEGR1, perfectly tagged by the lead SNPs in this region (including rs2815752 and rs2568958). Deletion of this segment removes regulatory sequences that drive NEGR1 expression, particularly in hypothalamic neurons in the NEGR1 upstream region that removes regulatory sequences controlling hypothalamic expression. Second, eQTL analyses in the Levey et al. 2021⁵⁵ Levey et al. 2021
Levey DF et al. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals. Nat Neurosci, 2021 dataset confirmed that the depression-risk allele at the NEGR1 locus acts as a brain eQTL: it statistically predicts lower NEGR1 mRNA abundance specifically in hypothalamic tissue. Less NEGR1 protein means less synaptic scaffolding in exactly the circuits that connect mood and appetite.

In animal models, NEGR1-deficient mice⁶⁶ NEGR1-deficient mice
Noh K et al. Negr1 controls adult hippocampal neurogenesis and affective behaviors. Mol Psychiatry, 2019 show severely impaired long-term potentiation in the hippocampal dentate gyrus, near-abolition of adult neurogenesis, and robust depression- and anxiety-like behaviors across validated assays. The mechanistic pathway proceeds through the LIFR–Lcn2 axis: NEGR1 activates the leukemia inhibitory factor receptor, which drives Lipocalin-2 production, which is itself required for hippocampal neurogenesis. Meanwhile, a 2022 study by Kaare et al.⁷⁷ Kaare et al.
Kaare M et al. Depression-Associated Negr1 Gene-Deficiency Induces Alterations in the Monoaminergic Neurotransmission. Brain Sciences, 2022 found dysregulated signaling across all three monoamine systems — elevated striatal dopamine release, altered hippocampal serotonin, and disrupted norepinephrine responses — confirming that NEGR1's role extends well beyond structural wiring into active neurotransmitter circuit organization.

The Evidence

The BMI evidence arrived first. In the landmark Willer et al. 2009⁸⁸ Willer et al. 2009
Willer CJ et al. Six new loci associated with body mass index. Nat Genet, 2009 meta-analysis of over 32,000 individuals, the NEGR1 locus reached genome-wide significance for BMI with an effect of approximately 0.05 SD units per allele (~0.36 kg/m²). Crucially, several of the identified loci — including NEGR1 — were expressed in the central nervous system, pointing to a neuronal rather than peripheral mechanism for their effect on body weight.

The depression evidence followed years later at far greater statistical power. The Howard et al. 2019⁹⁹ Howard et al. 2019
Howard DM et al. Genome-wide meta-analysis of depression identifies 102 independent variants. Nat Neurosci, 2019 study (N=807,553, including 246,363 cases) identified the NEGR1 locus at P=3.55×10⁻¹⁵ for major depression. This finding was further strengthened in the Levey et al. 2021¹⁰¹⁰ Levey et al. 2021
Levey DF et al. Bi-ancestral depression GWAS. Nat Neurosci, 2021 analysis (N=1,154,267) where the lead NEGR1 SNP reached P=8.9×10⁻²⁹ — one of the highest-confidence depression loci in the human genome.

The shared genetic signal was formally characterized by Zhang et al. 2024¹¹¹¹ Zhang et al. 2024
Zhang H et al. Dissecting shared genetic architecture between depression and body mass index. BMC Medicine, 2024: depression and BMI share a genetic correlation of rg=0.19 (P=4×10⁻²⁶), and among all shared loci, NEGR1 was the single most significant gene. Brain tissue from individuals with both depression and obesity showed the greatest reductions in NEGR1 expression, concentrated in the nucleus accumbens and anterior cingulate cortex — reward and emotional valuation centers.

Replication of rs2568958 specifically extends to African-American populations: Hester et al. 2011¹²¹² Hester et al. 2011
Hester JM et al. Implication of European-derived adiposity loci in African Americans. PLoS Genet, 2011 confirmed the rs2568958-BMI association (P<0.05) across six African-American cohorts (N=4,992), with effect sizes of 0.04–0.06 SD units per allele — demonstrating this is not a European-specific finding.

Practical Implications

For G-allele carriers, the actionable insight sits at the intersection of the two pathways NEGR1 organizes: hippocampal neurogenesis and hypothalamic monoamine architecture. Aerobic exercise is the most potent behavioral driver of BDNF-mediated hippocampal neurogenesis — directly compensating for reduced LIFR-Lcn2 signaling. Dietary protein provides the precursors (tryptophan for serotonin, tyrosine for dopamine/norepinephrine) that feed the monoamine circuits disorganized by NEGR1 reduction. Omega-3 EPA/DHA supports neuronal membrane fluidity and monoamine receptor function. The dual mood-metabolic nature of NEGR1 means interventions supporting one pathway tend to benefit both.

Interactions

Rs2568958 is one of several SNPs tagging the same NEGR1 risk locus — rs34579341, rs2815752, rs11209948, and rs7531118 are all in moderate-to-high linkage disequilibrium with it. Users who have results for rs34579341 are reading from the same causal signal. The depression signal at NEGR1 interacts with BDNF Val66Met (rs6265): since NEGR1 drives hippocampal neurogenesis through the LIFR-Lcn2 axis that converges on BDNF, carriers of both G at rs2568958 and Met at rs6265 face compounded neurogenic impairment. COMT (rs4680) represents a relevant monoaminergic interaction given the dopamine and norepinephrine dysregulation documented in NEGR1-deficient animals.