bio-causal-genomics-genomic-sem

name	bio-causal-genomics-genomic-sem
description	Fits structural equation models to GWAS summary statistics using GenomicSEM (Grotzinger 2019), including common-factor models, confirmatory factor models, ESEM, common-factor GWAS with Q_SNP heterogeneity, multivariate Wald tests, and stratified GenomicSEM partitioned heritability. Reconciles results against MTAG multi-trait analysis. Handles sample overlap via the LDSC sampling-covariance matrix, identifies and resolves Heywood cases, and verifies model fit with CFI / RMSEA. Use when modeling latent genetic architecture across correlated traits, running multivariate GWAS on a shared factor, distinguishing factor-mediated from trait-specific SNP effects, or comparing GenomicSEM common-factor results against MTAG when both depend on accurate sampling covariance.
tool_type	r
primary_tool	GenomicSEM

Version Compatibility

Reference examples tested with: GenomicSEM 0.0.5+ (GitHub GenomicSEM/GenomicSEM), lavaan 0.6-17+, LDSC v1.0.1+ (Python 3; prefer abdenlab/ldsc-python3 v2.0.0 -- belowlab/ldsc v3.0.1 README states the CLI is broken; Docker jtb114/ldsc:latest is the belowlab fallback), baselineLD_v2.2 annotations (alkesgroup.broadinstitute.org/LDSCORE), MTAG 1.0.8+ (Python; JonJala/mtag), R 4.4+.

Before using code patterns, verify installed versions match. If versions differ:

• R: packageVersion('GenomicSEM') then ?ldsc, ?commonfactor, ?usermodel, ?commonfactorGWAS
• Python (LDSC, MTAG): <tool>.py -h and inspect the source under ldsc/ or mtag/

GenomicSEM is GitHub-only (never on CRAN). If ldsc() or usermodel() throws an error about lavaan syntax or non-positive-definite covariance, introspect the installed API (getMethod('ldsc')) and adapt rather than retrying.

Genomic SEM

"Model the latent genetic architecture across several correlated GWAS" -> Treat each GWAS as a measured indicator of one or more latent genetic factors and fit a structural equation model to the LDSC-derived genetic covariance matrix S and its sampling covariance V (Grotzinger 2019 Nat Hum Behav 3:513). The framework extends naturally to a multivariate GWAS in which a SNP is regressed on a latent factor (common-factor GWAS), with Q_SNP testing whether the SNP effect is homogeneous across factor loadings. Sample overlap between input GWAS is absorbed by the off-diagonals of V; ignoring V inflates Type-I.

• R: GenomicSEM::ldsc() produces the (S, V) covariance pair from munged sumstats
• R: GenomicSEM::commonfactor() fits a single-factor CFA across all traits in S
• R: GenomicSEM::usermodel() fits an arbitrary lavaan-syntax model
• R: GenomicSEM::commonfactorGWAS() runs SNP -> factor multivariate GWAS with Q_SNP
• R: GenomicSEM::userGWAS() runs arbitrary multivariate SNP regression with per-path Q_SNP
• Python (alternative): mtag.py --sumstats t1,t2,t3 --out mtag_out (multi-trait power boost on individual traits)

Statistical Model Taxonomy

Method	Latent structure	Min traits	SNP-level test	Strength	Fails when
Common-factor CFA (Grotzinger 2019)	Single F loading all traits	3	None (model-fit only)	Tests whether shared variance is unidimensional	Heterogeneous architecture; CFI < 0.9; near-zero loadings
User-specified CFA (usermodel)	Pre-specified lavaan syntax	3	None	Confirmatory; arbitrary structure	Misspecified model; identification under-determined
ESEM	Exploratory rotation; cross-loadings allowed	6+	None	When factor count and structure unknown	Few traits; collinear traits; rotation arbitrary
Common-factor GWAS (commonfactorGWAS)	SNP -> F -> trait1..k	3	Wald on F + Q_SNP heterogeneity	Discovers SNPs acting via the common factor; flags Q_SNP outliers	Q_SNP-significant SNPs not interpretable as factor SNPs
User GWAS (userGWAS)	Arbitrary SNP-path lavaan	3	Wald per path + Q_SNP	Tests SNP on any specified path	Highly parameterized models lose power
Multivariate Wald test	Joint test across SNP -> trait paths	2+	Joint chi-square	Boost power when SNP affects multiple traits	Heterogeneous SNP effects collapse joint test
Stratified GenomicSEM (Grotzinger AD et al 2022 Nat Genet 54:548)	Factor model with sLDSC-partitioned annotations	3	Per-annotation factor tau	Localizes heritability of the factor to functional categories	Same sLDSC failure modes (small annotation, collinearity)
MTAG (Turley 2018 Nat Genet 50:229)	Empirical-Bayes shrinkage across correlated traits	2	Per-trait shrunk z-score	Boosts marginal power for any input trait	MaxFDR > 5% indicates heterogeneity violates MTAG assumption

Methodology evolves; verify the current Grotzinger 2023+ tutorials at github.com/GenomicSEM/GenomicSEM/wiki before locking a method. ESEM rotation choice (geomin vs target rotation) is an active area; report sensitivity to rotation.

MTAG vs GenomicSEM Common-Factor GWAS

Both methods exploit genetic correlation among input GWAS, but their goals and outputs differ.

Property	MTAG	GenomicSEM commonfactorGWAS
Output	Per-trait shrunk z-scores	SNP effect on latent factor
Sample-overlap handling	Bivariate LDSC intercept	Full LDSC sampling-covariance matrix V
Heterogeneity diagnostic	MaxFDR (Turley 2018)	Q_SNP (Grotzinger 2019)
Interpretation	"Boosted power for trait k"	"Effect on what the traits share"
Min traits	2	3 (otherwise factor not identified)
Best when	Power-boost an individual trait	Common factor hypothesized

Both depend on accurate sampling covariance. MTAG fails (MaxFDR > 5%) under the same heterogeneity that produces large Q_SNP in GenomicSEM. The two methods should be reported together when the prior on a common factor is non-trivial; agreement increases confidence, disagreement points to architecture-specific SNPs.

Decision Tree by Scenario

Scenario	Recommended	Why
Multi-trait GWAS power boost for one focal trait	MTAG	Optimized for per-trait marginal power
Common-factor architecture hypothesized	GenomicSEM commonfactorGWAS	Tests SNP -> factor; reports Q_SNP heterogeneity
Heterogeneous architecture (>1 latent factor)	ESEM, then confirmatory usermodel	Exploratory first, then confirm
Confirming a pre-specified factor structure	usermodel with lavaan syntax	Confirmatory factor analysis
Partition heritability of factor across annotations	Stratified GenomicSEM	Combines sLDSC + factor model
Mediation in a SEM framework	usermodel with indirect path	Path coefficients + delta-method SE
Sample overlap unknown or any-overlap suspected	Always use ldsc() output as input	V matrix off-diagonals absorb overlap
Cross-ancestry common-factor analysis	Run per-ancestry, compare loadings; no published cross-ancestry SEM as of 2026	Method not yet validated for mixed-ancestry V
Single biobank for all traits (e.g., UKB only)	GenomicSEM with ldsc(); the V matrix will reflect overlap	Equivalent to one-sample MR -- the V matrix is the correction
Comparing GenomicSEM and MTAG on the same traits	Run both; compare top hits + heterogeneity	Concordance increases confidence; divergence flags heterogeneity

Per-Method Failure Modes

Heywood case (negative residual variance)

Trigger: A residual variance estimate is < 0, or a standardized loading exceeds 1.

Mechanism: Empirical underidentification; the genetic covariance matrix S is near-singular OR a trait has near-zero specific variance under the model. The maximum-likelihood / DWLS estimator runs past the boundary of the parameter space.

Symptom: lavaan warning "some estimated lv variances are negative" or "covariance matrix is not positive definite"; standardized loading > 1; non-convergence.

Fix: First, inspect the LDSC S matrix for genetic correlations near 1 (multicollinearity). Drop or merge near-identical traits. Second, constrain the offending residual variance to be non-negative in the lavaan syntax (trait1 ~~ a*trait1; a > 0). Third, verify the V matrix is positive definite via chol(V_LD); if not, the bivariate LDSC inputs disagree on intercept signs and need re-munging. Never re-fit without diagnosing the cause.

Sample overlap mis-specified

Trigger: Using LDSC intercept manually or supplying covariance from non-ldsc() source.

Mechanism: GenomicSEM's ldsc() function returns a list with S (genetic covariance) AND V (sampling covariance of the lower-triangle of S). The V off-diagonals capture sample overlap via cross-trait LDSC intercept. Skipping V and supplying only S treats all inputs as independent samples; Type-I error inflates because the sampling distribution under H0 is wrong.

Symptom: SE on factor loadings far too small; many SNPs significant in common-factor GWAS that don't replicate; comparison to MTAG shows disagreement consistent with overlap.

Fix: Always pass the full output of ldsc() -- both S and V -- to commonfactor(), usermodel(), and commonfactorGWAS(). Never construct S manually from rg estimates.

Q_SNP not reported in commonfactorGWAS

Trigger: Running commonfactorGWAS() and reporting only the factor p-value per SNP.

Mechanism: Q_SNP tests heterogeneity of the SNP's effect across factor loadings (Grotzinger 2019 supplement). A SNP with significant Q_SNP violates the common-factor assumption: its effect is NOT mediated by the factor, and the factor estimate is meaningless for that SNP.

Symptom: Top "common-factor SNPs" are dominated by trait-specific effects; replication in independent cohorts is poor for SNPs with high Q_SNP.

Fix: Always report Q_SNP p-value alongside the factor p-value. Flag SNPs with Q_SNP p < 5e-8 / N_factor_SNPs (Bonferroni for the discovered set) as architecture-violating and exclude from "common-factor SNP" claims. Re-fit those SNPs in userGWAS() with separate paths to each trait.

Trait inclusion under heterogeneous factor structure

Trigger: Forcing a common-factor model on traits that don't share a single latent factor.

Mechanism: When two or more traits load on a different factor than the rest, the single-factor model misfits. lavaan still returns parameter estimates but model fit is poor.

Symptom: CFI < 0.9; RMSEA > 0.08; some standardized loadings near 0 while others near 1; chi-square highly significant even after accounting for N.

Fix: Run ESEM first (commonfactor then usermodel with cross-loadings allowed) to discover structure. If two factors emerge, fit a two-factor usermodel. Drop traits with near-zero loadings on all factors. Document the model search.

MTAG MaxFDR > 5%

Trigger: Running MTAG on traits with low pairwise genetic correlation or with one trait that has a very different architecture.

Mechanism: MTAG assumes a homogeneous variance-covariance structure across SNPs. When heterogeneity dominates, the empirical-Bayes shrinkage can over-claim SNPs in the focal trait. Turley 2018 defines MaxFDR as the maximum estimated false discovery rate under worst-case heterogeneity; > 5% invalidates the published trait-specific summary statistics.

Symptom: MTAG output file reports maxFDR > 0.05; per-trait MTAG hits don't replicate in independent cohorts.

Fix: Check pairwise rg via LDSC; if any pair is < 0.7, MTAG is risky. Drop the most heterogeneous trait and re-run. Alternatively, switch to GenomicSEM's commonfactorGWAS which models heterogeneity explicitly via Q_SNP.

Non-positive-definite V_LD matrix

Trigger: LDSC inputs from different ancestry GWAS, or one trait with very low mean chi-square (< 1.02).

Mechanism: V is the sampling covariance of vech(S); when individual entries of S have huge SE relative to off-diagonal covariance, the resulting V is not positive definite (negative eigenvalues).

Symptom: commonfactor() errors with "matrix is not positive definite" before fitting; eigen(LDSCoutput$V)$values shows negative values.

Fix: Verify per-trait mean chi-square via ldsc() log; below 1.02, exclude that trait. Verify all GWAS are EUR ancestry (or match ancestry of LD scores). Apply nearest-PD smoothing via Matrix::nearPD(V)$mat ONLY as a last resort and document the approximation in methods.

Model Fit Diagnostics

Index	Acceptable	Good	Source
CFI	>= 0.90	>= 0.95	Hu & Bentler 1999 Struct Equ Model 6:1
TLI / NNFI	>= 0.90	>= 0.95	Hu & Bentler 1999
RMSEA	<= 0.08	<= 0.05	Hu & Bentler 1999
SRMR	<= 0.08	<= 0.05	Hu & Bentler 1999
chi-square p-value	(less informative at large N)	n/a	Penalize for N inflation

AIC / BIC are used for nested-model comparison (lower is better); only compare nested models fit on the same S.

Quantitative Thresholds

Threshold	Source	Rationale
CFI >= 0.95	Hu & Bentler 1999	Conventional good fit; SEM literature default
RMSEA <= 0.05	Hu & Bentler 1999	Conventional good fit
RMSEA 0.05 - 0.08	Hu & Bentler 1999	Acceptable; flag as "adequate" not "good"
Q_SNP p < 0.05 / N_SNP_factor	Grotzinger 2019 Nat Hum Behav 3:513	Bonferroni for heterogeneity among factor-significant SNPs
MTAG MaxFDR < 5%	Turley 2018 Nat Genet 50:229	Above this, MTAG marginal trait results invalid
Per-trait LDSC mean chi-square > 1.02	LDSC documentation	Below this, V entries too noisy; factor SE inflated
Standardized loading 0.3 - 0.9 typical	SEM conventions	< 0.3 trait loads weakly; > 0.95 may indicate over-fit / collinearity
Min 3 traits for common factor	SEM identification	Single factor with k traits has k(k+1)/2 moments; needs k>=3 to identify

Standard Workflow

Goal: Fit a common-factor model across correlated GWAS and run a multivariate GWAS on the factor with Q_SNP.

Approach: Munge sumstats -> LDSC for (S, V) -> common-factor CFA -> inspect fit -> prepare SNPs -> common-factor GWAS -> report factor effects with Q_SNP flags.

library(GenomicSEM)

# Step 1: Munge sumstats (one-time; produces .sumstats.gz files)
files <- c('raw/trait1.txt', 'raw/trait2.txt', 'raw/trait3.txt')
hm3 <- 'w_hm3.snplist'  # HapMap3 SNP list
trait_names <- c('trait1', 'trait2', 'trait3')
N <- c(150000, 200000, 175000)
munge(files = files, hm3 = hm3, trait.names = trait_names, N = N)

# Step 2: LDSC produces both S (genetic covariance) and V (sampling covariance)
traits <- c('trait1.sumstats.gz', 'trait2.sumstats.gz', 'trait3.sumstats.gz')
ldsc_results <- ldsc(
    traits  traits
    sample.prev        
    population.prev    
    ld  
    wld  
    trait.names  trait_names




cf_fit  commonfactorcovstruc  ldsc_results estimation  
printcf_fitmodelfit  
printcf_fitresults   




model_syntax  
user_fit  usermodelcovstruc  ldsc_results model  model_syntax estimation  

estimation = 'DWLS' (diagonally weighted least squares) is the default and is required when V is large; 'ML' is faster but assumes a known V and can produce wrong SE under sample overlap.

ESEM (Exploratory Factor Structure)

When the factor structure is unknown, fit usermodel() with all loadings free across all factors, then apply a rotation post-fit. Rotation choices: geomin oblique (default; allows factor correlation), target rotation (Browne 2001 Multivariate Behav Res 36:111; uses a hypothesized loading template), quartimin (orthogonal; assumes factors are uncorrelated).

model_esem <- '
    F1 =~ NA*trait1 + trait2 + trait3 + trait4
    F2 =~ NA*trait1 + trait2 + trait3 + trait4
    F1 ~~ 1*F1
    F2 ~~ 1*F2
    F1 ~~ F2
'
esem_fit <- usermodel(covstruc = ldsc_results, model = model_esem, estimation = 'DWLS')
# Rotate post-fit via GPArotation::GPForth/GPFoblq or lavaan::rotate()

Decision: ESEM for K-factor exploration when structure is unknown; CFA via usermodel() once a structure is confirmed. Report rotation sensitivity (geomin vs target vs quartimin) and treat as exploratory.

Cross-loadings. Cross-loadings (one trait loads on > 1 factor) are common in psychiatric and behavioral GWAS. Brown 2015 Confirmatory Factor Analysis for Applied Research recommends allowing cross-loadings first and using modification indices to guide simplification. Allow a cross-loading when constraining residual variance otherwise forces a Heywood case. Constrain when CFI < 0.9 and modification indices instead suggest a correlated residual between two indicators (which is the more parsimonious fix).

userGWAS for Custom Path Models

userGWAS() fits arbitrary lavaan-syntax SNP regressions and is the right tool when the SNP needs to be tested on multiple paths simultaneously (e.g. factor-mediated effect AND a direct effect on one indicator).

# Test SNP -> F path + SNP -> trait1 direct path simultaneously
model <- '
    F =~ NA*trait1 + trait2 + trait3
    F ~~ 1*F
    F ~ SNP
    trait1 ~ SNP    # direct effect on trait1, partialed out of F
'
user_results <- userGWAS(covstruc = ldsc_results,
                         SNPs = ss,
                         estimation = 'DWLS',
                         model = model,
                         sub = c('F~SNP', 'trait1~SNP'),
                         parallel = TRUE,
                         cores = 8)
# Output columns include: lhs, op, rhs, est, SE, Z, Pvalue, Q_pval, Q_df.
# Q_pval per SNP measures heterogeneity across loadings AFTER conditioning on
# the direct path; remaining Q_SNP signal indicates a third path is needed.

Higher-Order / Bifactor / p-Factor Models

Use case: psychiatric genetics p-factor (Caspi 2014 Clin Psychol Sci 2:119; Grotzinger 2022 Nat Genet 54:548 cross-disorder), cognitive g-factor (de la Fuente 2021 Nat Hum Behav 5:49).

Hierarchical template -- first-order factors load on a single second-order p-factor:

model_pfactor <- '
    # First-order factors
    INT =~ NA*trait_anx + trait_dep + trait_neuro       # internalizing
    EXT =~ NA*trait_adhd + trait_alc + trait_subst       # externalizing
    THT =~ NA*trait_scz + trait_bp                       # thought-disorder
    # Second-order p-factor
    p =~ NA*INT + EXT + THT
    INT ~~ 1*INT
    EXT ~~ 1*EXT
    THT ~~ 1*THT
    p ~~ 1*p
'

Bifactor alternative: p =~ all traits directly, with INT/EXT/THT as orthogonal residual factors. Bifactor typically gives tighter CFI/RMSEA but the substantive interpretation of the residual factors is harder; bifactor is also prone to over-fitting at modest trait counts (Bonifay W & Cai L 2017 Multivariate Behav Res 52:465). Cite Grotzinger 2022 Nat Genet 54:548 and Karlsson Linner R, Mallard TT et al 2021 Nat Neurosci 24:1367 for the canonical psychiatric implementations.

Common-Factor GWAS with Q_SNP

Goal: Identify SNPs that affect the latent factor and flag SNPs whose effect is heterogeneous across loadings.

Approach: Build SNP-by-trait effect-and-SE matrix via sumstats(), then fit the SNP-augmented model genome-wide via commonfactorGWAS(). Report both factor p-value and Q_SNP p-value per SNP.

sumstats() flips effect signs based on the reference panel A1/A2 to enforce consistent allele coding across input GWAS. Required input columns (case-sensitive) are SNP, A1, A2, BETA/Z/OR, SE, P, N, MAF; some are conditional on se.logit / OLS. Silent failures are almost always column-name mismatches (e.g. EA/NEA instead of A1/A2 -> 0% SNPs retained) or a missing N column -> SNPs dropped. Always run head(read.table(file, header=TRUE, nrow=2)) per input before the sumstats() call.

# Prepare per-SNP betas and SEs across all input GWAS
ss <- sumstats(
    files = c('raw/trait1.txt', 'raw/trait2.txt', 'raw/trait3.txt'),
    ref = 'reference.1000G.maf.0.005.txt',
    trait.names = trait_names,
    se.logit = c(TRUE, TRUE, FALSE),     # TRUE if trait is logistic-scale (case-control); FALSE if continuous
    OLS = c(FALSE, FALSE, TRUE),
    linprob = c(FALSE, FALSE, FALSE),
    N = N,
    info.filter = 0.9,                   # standard imputation INFO threshold
    maf.filter  






cfgwas  commonfactorGWAS
    covstruc  ldsc_results
    SNPs  ss
    estimation  
    parallel  
    cores  
    MPI  





cfgwasfactor_sig  cfgwasPval_Estimate  
cfgwasqsnp_sig  cfgwasQ_pval    cfgwasfactor_sig
cfgwasfactor_only  cfgwasfactor_sig  cfgwasqsnp_sig

The "factor-only" subset (factor-significant AND Q_SNP non-significant) is the publication-grade set of common-factor SNPs.

MTAG Comparison

Goal: Cross-check GenomicSEM common-factor results against MTAG per-trait shrunk z-scores.

Approach: Run MTAG CLI on the same input sumstats; compare top hits with GenomicSEM factor hits. Report MaxFDR.

# MTAG CLI (Python)
python mtag.py \
    --sumstats trait1.txt,trait2.txt,trait3.txt \
    --n_min 0 \
    --out mtag_results
# MTAG uses the signed Z by default; --use_beta_se was disabled upstream (raises a
# RuntimeError since Dec 2021 due to beta-se bugs), so supply a Z column and omit it.

# Check MaxFDR per trait
grep -iE 'max ?fdr' mtag_results.log   # matches both the section header and the 'Max FDR of Trait' value lines
# Each per-trait MTAG file: mtag_results_trait_<k>.txt

If MaxFDR > 0.05 for any trait, MTAG results for that trait are unreliable; GenomicSEM with Q_SNP filtering is the more defensible report.

Stratified GenomicSEM (Partitioned Heritability of Factor)

For partitioning the heritability of the latent factor across functional annotations, use s_ldsc() (stratified LDSC inside GenomicSEM) and pass the multi-annotation output to a stratified model fit.

# Stratified LDSC across baseline + custom annotations
s_results <- s_ldsc(
    traits = traits,
    sample.prev = c(0.5, 0.5, NA),
    population.prev = c(0.05, 0.05, NA),
    ld = 'baselineLD_v2.2.',
    wld = 'weights.hm3_noMHC.',
    frq = '1000G.EUR.QC.',
    trait.names = trait_names
)

# enrich() inventory:
#   params: lavaan syntax of the parameter under enrichment (loading, residual var, or F~~F latent var)
#   fix='regressions': hold regression paths fixed at the genome-wide estimate during stratified fit
#   std.lv=FALSE: do not standardize the latent variance
#   rm_flank=TRUE: drop flanking-window contributions (default)
#   tau=FALSE: use the baseline-annotation S/V matrices (TRUE switches to the V_Tau/S_Tau tau parametrization)
#   base=TRUE: include baseline annotation contributions in the partition
#   toler=NULL: matrix-inversion tolerance (let GenomicSEM choose; supply a small value when S is near-singular)
strat_factor <- enrichs_covstruc  s_results
                       model  
                       params  
                       fix  
                       std.lv  
                       rm_flank  
                       tau  
                       base  
                       toler  

The output gives per-annotation enrichment of the factor h2 -- the analog of cell-type S-LDSC for the latent factor (Grotzinger AD et al 2022 Nat Genet 54:548).

Computational Footprint

Step	Runtime	Hardware
ldsc() multi-trait sampling covariance	minutes	laptop
commonfactor() / usermodel() (no SNP loop)	seconds	laptop
commonfactorGWAS() over 6-8M SNPs	4-24h depending on cores	cluster recommended
userGWAS() over 6-8M SNPs with complex path model	8-48h	cluster recommended
Stratified GenomicSEM with 50+ annotations	1-3 days	cluster
MTAG over 6-8M SNPs	1-2h	laptop or cluster

Cluster runs of commonfactorGWAS() / userGWAS() should use MPI=TRUE when submitting via mpirun; GenomicSEM detects the OS internally (via Sys.info()[['sysname']]) and selects FORK (Linux/Mac) vs PSOCK (Windows) cluster types automatically -- there is no Operating= user argument. On a Mac/Windows workstation, reduce cores to the physical-core count to avoid PSOCK fork failures.

Reconciliation: When GenomicSEM and MTAG Disagree

Pattern	Likely cause	Action
GenomicSEM factor SNP sig, MTAG sig for all traits	Genuine common-factor SNP	Report; high confidence
GenomicSEM factor SNP sig, MTAG sig in only 1 trait	Q_SNP heterogeneity likely; one-trait-dominant	Check Q_SNP; if sig, this is NOT a factor SNP
MTAG sig, GenomicSEM factor null, Q_SNP sig	Trait-specific SNP captured by MTAG shrinkage	Report as trait-specific, not common-factor
Both null but per-trait univariate sig	Power loss from multivariate parameterization	Re-check sample overlap V matrix
GenomicSEM and MTAG both sig but opposite direction	Sample-overlap mis-specification OR sign error in munging	Re-munge with same allele convention; re-run ldsc()
MTAG MaxFDR > 5%, GenomicSEM with Q_SNP works	MTAG assumption violated	Prefer GenomicSEM as primary
One-trait GWAS sig but common-factor not	Trait-specific architecture	Don't force into common-factor frame

Operational rule for publication: A common-factor SNP claim requires (1) factor p < 5e-8, (2) Q_SNP p > 0.05 / N_factor_SNPs (non-heterogeneous), and (3) replication in an independent set of traits or cohorts. Trait-specific SNPs from MTAG require MaxFDR < 5% for the trait. Reporting only the factor effect without Q_SNP is the most common reviewer-flagged error.

Common Errors

Error / symptom	Cause	Solution
commonfactor() complains "S not positive definite"	Genetic correlations near +/-1 among inputs	Drop redundant traits; verify rg < 0.95 pairwise
Standardized loading > 1	Heywood case; under-identification	Constrain residual variance >= 0; inspect S for collinearity
Factor p-value reported, Q_SNP not reported	Default focus is on factor effect	Always report Q_SNP from commonfactorGWAS output
ldsc() fails with "category not found"	Wrong LD score column names (legacy format)	Use Python 3 LDSC fork; download eur_w_ld_chr/ from alkesgroup
lavaan says "model not identified"	Too few traits for too many parameters	Need >= 3 traits per factor; constrain factor variance to 1
MTAG MaxFDR not in log	Older MTAG version (< 1.0.7)	Update MTAG; MaxFDR reporting added late 2019
Singular V matrix on smooth nearPD	One trait has near-zero h2 or mean chi-square < 1.02	Drop the trait; do not smooth as a fix
usermodel() slow or fails	Complex syntax + many traits	Simplify model; estimate with estimation = 'DWLS', not 'ML', when V is informative
Sumstats output has zero overlap with reference	Allele coding mismatch in sumstats()	Check se.logit and OLS settings per trait; align A1/A2
GenomicSEM and TwoSampleMR give different rg	TwoSampleMR uses bivariate LDSC; GenomicSEM uses the same S	Match the underlying LDSC reference panel and weights

Anticipated Reviewer Pushback

Pushback	Standard response
"Q_SNP reported?"	Q_pval column reported alongside SNP->factor effect; Bonferroni threshold 5e-8 / N_factor_SNPs applied
"MaxFDR > 5%?"	MTAG maxFDR reported per trait; > 5% invalidates MTAG for that trait -> GenomicSEM common-factor used instead
"Sample overlap absorbed?"	Full V matrix from ldsc() is the input to all model fits; S is never constructed manually from pairwise rg estimates
"Model fit?"	CFI >= 0.95, RMSEA <= 0.08, SRMR <= 0.08 reported; AIC / BIC for nested comparison; chi-square reported but treated as inflated at large N
"Why a factor model and not MTAG?"	Factor structure tested first; if traits load on a common factor with CFI > 0.95, common-factor GWAS preferred -- explicitly models heterogeneity via Q_SNP
"Heywood case?"	Negative residual variance constrained >= 0; OR the offending indicator dropped and the model re-specified; the choice is documented in methods
"Cross-ancestry?"	Run per-ancestry; no validated cross-ancestry V matrix as of 2026; loadings compared qualitatively
"Why DWLS and not ML?"	ML assumes V is known; DWLS uses the empirical V from ldsc() and is the appropriate estimator under sample overlap

Tool Installation

# GenomicSEM is GitHub-only
remotes::install_github('GenomicSEM/GenomicSEM')

# Dependencies
install.packages(c('lavaan', 'Matrix', 'gdata'))

# Optional companions
remotes::install_github('MRCIEU/TwoSampleMR')  # for downstream MR using factor GWAS as exposure

For Python tools:

# LDSC python3 fork (GenomicSEM input format). belowlab/ldsc v3.0.1 broke the
# --h2/--rg/--h2-cts CLI per its README; use abdenlab/ldsc-python3 (v2.0.0)
# for a working CLI. Docker jtb114/ldsc:latest is the belowlab fallback.
git clone https://github.com/abdenlab/ldsc-python3.git
cd ldsc-python3 && pip install .   # Poetry project (pyproject.toml); no requirements.txt

# MTAG
git clone https://github.com/JonJala/mtag.git
cd mtag && pip install -r requirements.txt

Pre-downloaded reference files: eur_w_ld_chr/, baselineLD_v2.2.*, w_hm3.snplist, and 1000G allele-frequency files are hosted at alkesgroup.broadinstitute.org/LDSCORE/.

References

• Grotzinger AD et al 2019 Nat Hum Behav 3:513 (GenomicSEM, common-factor GWAS, Q_SNP)
• Grotzinger AD et al 2022 Nat Genet 54:548 (Stratified GenomicSEM)
• Turley P et al 2018 Nat Genet 50:229 (MTAG; MaxFDR)
• Bulik-Sullivan B et al 2015 Nat Genet 47:291 (LDSC for genetic covariance)
• Bulik-Sullivan B et al 2015 Nat Genet 47:1236 (bivariate LDSC, sample overlap)
• Rosseel Y 2012 J Stat Softw 48:1-36 (lavaan package)
• Hu LT & Bentler PM 1999 Struct Equ Model 6:1 (CFI / RMSEA cutoffs)
• Asparouhov T & Muthen B 2009 Struct Equ Model 16:397 (ESEM framework)
• Finucane HK et al 2015 Nat Genet 47:1228 (S-LDSC, foundation for stratified GenomicSEM)
• Gazal S et al 2017 Nat Genet 49:1421 (baseline-LD annotations)
• Demange PA et al 2021 Nat Genet 53:35 (GenomicSEM GWAS-by-subtraction for noncognitive skills; Q_SNP in practice)
• Karlsson Linner R, Mallard TT et al 2021 Nat Neurosci 24:1367 (multivariate externalizing GWAS via GenomicSEM)
• de la Fuente J et al 2021 Nat Hum Behav 5:49 (GenomicSEM for cognitive g factor)
• Skrivankova VW et al 2021 JAMA 326:1614 (STROBE-MR; relevant when downstream MR uses factor GWAS)

Related Skills

• causal-genomics/mendelian-randomization - Use factor-GWAS effect sizes as MR exposure
• causal-genomics/genetic-correlation - Bivariate LDSC produces the off-diagonals of the S matrix; GenomicSEM is the multi-trait extension
• causal-genomics/heritability-partitioning - LDSC and S-LDSC foundations for stratified GenomicSEM
• causal-genomics/colocalization-analysis - Cross-trait colocalization at common-factor loci
• causal-genomics/pleiotropy-detection - Q_SNP is a per-SNP pleiotropy diagnostic; sibling concept
• causal-genomics/fine-mapping - Resolve factor-significant loci to credible sets
• causal-genomics/mediation-analysis - SEM mediation paths overlap with usermodel indirect effects
• causal-genomics/transcriptome-wide-association - TWAS on factor sumstats from commonfactorGWAS
• population-genetics/association-testing - GWAS sumstats are the input format