rs2605100 — LYPLAL1

LYPLAL1 and Fat Distribution: A Sex-Dimorphic Signal at Chromosome 1q41

Where you store fat matters as much as how much fat you carry. Two people with identical BMIs can have very different metabolic and health profiles depending on whether fat accumulates centrally (around the abdomen) or peripherally (in the hips, buttocks, and legs). The LYPLAL1 locus on chromosome 1q41 is one of the earliest and most replicated genetic signals for waist-hip ratio adjusted for BMI¹¹ waist-hip ratio adjusted for BMI
WHR-adjBMI is a phenotype that captures fat distribution independently of total adiposity — it reflects where fat is located, not how much there is, and its effects are dramatically stronger in women than in men.

rs2605100 sits within an intronic region of the LYPLAL1 antisense RNA 1 gene (LYPLAL1-AS1), approximately 259 kb from the LYPLAL1 protein-coding gene itself. LYPLAL1 (Lysophospholipase-Like 1) encodes a serine hydrolase with unclear endogenous substrate²² serine hydrolase with unclear endogenous substrate
Crystal structure shows LYPLAL1 is structurally similar to acyl-protein thioesterases but with a closed hydrophobic tunnel preferring short acyl chains; it has been proposed to act as a triglyceride lipase in adipose tissue and to regulate protein depalmitoylation. Despite its name, the protein is not a classical lysophospholipase. Its precise physiological substrate and pathway remain under active investigation.

The Mechanism

The G allele at rs2605100 is the major allele (frequency ~71% in Europeans, up to ~89% in Africans) and is the variant associated with higher WHR — meaning more centrally distributed fat — in women. The A allele is the protective (favorable) form linked to a more gynoid (hip-and-thigh-predominant) fat distribution pattern. The variant likely acts as a regulatory signal rather than directly altering the LYPLAL1 protein sequence, possibly influencing the expression of LYPLAL1 or its antisense RNA in adipose tissue.

Mouse knockout studies³³ Mouse knockout studies
CRISPR-Cas9 whole-body Lyplal1 KO on high-fat/high-sucrose diet; n=20 per sex per diet demonstrate a sex-specific role: female (but not male) Lyplal1 KO mice on a high-fat, high-sucrose diet weighed approximately 5 g less than wildtype controls, had reduced total body fat percentage, and showed smaller white adipose tissue depots across inguinal, gonadal, and perirenal sites. This mirrors the human GWAS pattern where LYPLAL1 variants affect fat distribution exclusively or predominantly in women. One proposed mechanism is that LYPLAL1 functions as an acyl thioesterase involved in protein palmitoylation⁴⁴ protein palmitoylation
Palmitoylation is the reversible attachment of palmitate to cysteine residues, which regulates membrane targeting and activity of proteins including estrogen receptors and metabolic signaling intermediates, potentially influencing estrogen receptor localization and thus coupling the gene's function to sex hormone signaling.

The Evidence

The original discovery came from a meta-analysis of 38,580 individuals⁵⁵ meta-analysis of 38,580 individuals
Lindgren et al. 2009, PLoS Genetics; 32 GWAS cohorts in stage 1, followed by replication in 70,689 subjects that identified rs2605100 as the sentinel variant at the LYPLAL1 locus. The association with WHR reached genome-wide significance in women (p = 1.3×10⁻⁸) but was completely absent in men (p = 0.50). The absolute effect — 0.0014 units of WHR per G allele — is modest, explaining approximately 0.02% of WHR variance in women. This is typical for GWAS hits: individually small effects that are biologically real and replicated.

A subsequent GIANT consortium analysis⁶⁶ subsequent GIANT consortium analysis
Heid et al. 2010, Nature Genetics; n=77,167 discovery, n=113,636 replication; 32 genome-wide association studies confirmed the LYPLAL1 signal alongside 13 newly discovered loci. Seven of the 14 confirmed WHR loci showed marked sex dimorphism, all with stronger effects in women — a pattern consistent with the well-established sex differences in adipose tissue distribution driven by estrogen signaling.

Metabolic consequences of the G allele extend beyond fat location. In a Danish population study⁷⁷ Danish population study
Dalgaard et al. 2011, PLoS ONE; Inter99 cohort, n=6,038 adults, each additional G allele was associated with 3% higher fasting triglycerides (p = 0.003), 3% higher fasting insulin (p = 0.003), and 4% higher HOMA-IR (p = 0.001). Notably, the triglyceride effect was male-restricted (6% per G allele in men, p = 2.4×10⁻⁴; interaction p = 0.02), suggesting different metabolic routes through which the variant affects men vs. women.

Evidence from bariatric surgery outcomes⁸⁸ bariatric surgery outcomes
Lund et al. 2016, n=251 RYGB patients (186 women); rs4846567, which is in high LD with rs2605100 shows that individuals homozygous for the favorable T allele of the correlated SNP rs4846567 lost 7% more excess body weight after gastric bypass surgery and reported 74% lower hunger scores and 53% lower disinhibition scores on validated eating behavior questionnaires compared to G-allele carriers.

Overall, evidence for rs2605100 is strong: multiple large, independent GWAS in European and Asian populations, consistent replication, plausible biological mechanism supported by animal models, and metabolic downstream effects that extend beyond the index phenotype.

Practical Actions

For carriers of one or two copies of the G allele — particularly women — the key insight is a genetic tendency toward central fat redistribution. This does not override lifestyle factors but does establish a meaningful background predisposition. Two areas are specifically supported by the biological evidence:

First, triglyceride management is directly implicated. The G allele is associated with elevated fasting triglycerides regardless of fat distribution. Dietary approaches that specifically lower triglycerides — not generic "healthy eating" — are warranted: reducing refined carbohydrate and added sugar intake, increasing omega-3 fatty acids (EPA/DHA from marine sources), and limiting alcohol.

Second, body composition monitoring matters more than scale weight. Since the LYPLAL1 locus affects fat distribution rather than total fat mass, standard BMI tracking misses the relevant phenotype. Waist circumference and waist-hip ratio track the fat depot that this variant influences most directly.

Interactions

The LYPLAL1 locus signal is most commonly indexed by rs4846567, which is in high linkage disequilibrium⁹⁹ linkage disequilibrium
LD means the two variants are almost always co-inherited; knowing your rs2605100 genotype reliably predicts your rs4846567 genotype with rs2605100. For practical interpretation, the two variants can be treated as equivalent.

The LYPLAL1 fat distribution signal operates independently of FTO/MC4R total adiposity signals — having a high-risk FTO genotype (rs9939609 AA) drives increased overall fat mass, while LYPLAL1 determines where that fat is preferentially stored. These can compound: an individual with high-risk genotypes at both loci may gain more total fat and distribute it more centrally.

Supervisor note — candidate compound action: individuals carrying the G allele at rs2605100 (LYPLAL1, central redistribution) AND the AA genotype at rs9939609 (FTO, higher total fat mass) represent the highest-risk combination for central obesity among these two loci. A combined recommendation addressing both elevated total fat accumulation and its central distribution — specifically targeting fasting triglycerides and waist circumference rather than weight alone — would be appropriate and supported by additive effects documented in stratified GWAS analyses.