rs2605100 — LYPLAL1

Intronic variant in the LYPLAL1 locus associated with waist-hip ratio and fat distribution, with sex-dimorphic effects strongest in women

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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.

Nutrient Interactions

dietary fat altered_metabolism
triglycerides increased_need

Genotype Interpretations

What each possible genotype means for this variant.

AA Favorable Fat Distribution Normal

Minor A allele associated with a more gynoid fat distribution pattern and lower waist-hip ratio in women

The AA genotype sits at the favorable end of the LYPLAL1 fat distribution spectrum. Genome-wide association studies consistently show that A allele carriers at this locus have lower waist-hip ratios compared to G allele carriers, specifically in women — the effect in men is not statistically significant. The absolute difference is approximately 0.003 units of WHR (two allele doses), which is modest at the individual level but reflects a genuine difference in adipose tissue partitioning between central and peripheral depots.

In mouse knockout experiments (Lyplal1 deletion — which mimics loss of this gene's function), female mice on a high-fat, high-sucrose diet were protected from weight gain and had reduced white adipose tissue in inguinal, gonadal, and perirenal depots. The knockout phenotype was completely absent in male mice, supporting the human GWAS finding that LYPLAL1's effects are female-specific.

The AA genotype is also linked, via the correlated variant rs4846567, to lower hunger and disinhibition scores — reduced biological drive to overeat — which may partly explain the better bariatric surgery outcomes seen in A allele homozygotes.

AG Moderate Central Tendency Intermediate

One G allele associated with modest tendency toward central fat distribution and modestly elevated triglycerides

Heterozygous AG carriers occupy the middle of the LYPLAL1 fat distribution spectrum. The GIANT consortium WHR meta-analysis (n=77,167 primary, n=113,636 replication) confirmed that the LYPLAL1 G allele effect on fat distribution is additive, meaning one G allele produces approximately half the effect of two.

Metabolic downstream effects of the G allele documented in the Danish Inter99 cohort include elevated fasting triglycerides (3% per allele, p=0.003), elevated fasting insulin (3% per allele, p=0.003), and elevated HOMA-IR (4% per allele, p=0.001). These are modest individual-level effects that nonetheless indicate a real metabolic consequence of the variant beyond its effect on fat location.

The sex-specific nature of the WHR effect is a robust finding: across the original discovery study (Lindgren 2009) and the larger GIANT consortium replication (Heid 2010), associations with WHR consistently reached genome-wide significance in women but not men, despite larger male sample sizes in some cohorts.

GG Central Fat Tendency High Risk

Two G alleles associated with the highest LYPLAL1-driven tendency toward central fat distribution and elevated triglycerides in women

The GG genotype represents the high-risk end of the LYPLAL1 spectrum, though it is paradoxically the most common genotype globally because G is the major allele at this SNP. The waist-hip ratio increase attributed to two G alleles (approximately 0.003 units in women) is modest in absolute terms but reflects a real difference in adipose tissue partitioning documented across dozens of independent GWAS cohorts.

The biological basis likely involves LYPLAL1's role as a serine hydrolase in adipose tissue. Mouse experiments show female-specific effects of Lyplal1 function: when the gene is knocked out in female mice on a high-fat diet, they accumulate significantly less white fat, with smaller adipocytes across multiple depots. This suggests LYPLAL1 normally promotes fat accumulation in women — particularly in peripheral depots under physiological conditions, but potentially shifting toward central depots when regulation is altered by variants like rs2605100.

The metabolic downstream effects in GG carriers are clinically meaningful in aggregate: elevated fasting triglycerides (6% per allele in men, 3% in pooled analyses), elevated fasting insulin (~3%), and elevated HOMA-IR (~4%). Over time, chronically elevated triglycerides and insulin resistance contribute to atherogenic dyslipidemia risk and increase cardiovascular disease risk independent of LDL cholesterol.

Evidence from bariatric surgery studies (rs4846567, high LD) suggests that GG-equivalent carriers have higher hunger scores and lower post-surgical weight loss than A allele carriers, suggesting a possible central appetite regulation component to LYPLAL1 function that compounds the fat distribution effect.