Steen 2025 — Familial coaggregation of FM with immune-related and cardiometabolic disease (Lifelines n=166,774) — H4/H5 cohort-overlap evidence

One-paragraph summary

Population-based cohort study using the Dutch Lifelines cohort (n=166,774 subjects aged 3–94 years across three generations). Functional disorders examined: ME/CFS, fibromyalgia, IBS. Internalizing disorders: MDD, GAD. Cardiometabolic disease: obesity, MASLD, T2DM, hypertension, CVD. Immune-related disease: composite measures of autoimmune disease and atopy. Statistical methods: recurrence risk ratios (λR) and familial correlations (rf). Key findings: (1) all functional and internalizing disorders co-aggregate with immune-related diseases (λR 1.06-1.24); (2) ME/CFS, FM, and MDD co-aggregate with most cardiometabolic diseases (λR 1.00-1.23); (3) MDD, FM, and ME/CFS show similar familial correlation patterns with both disease groups (rf 0.12-0.44). First population-scale evidence that FM has familial co-aggregation with both H4 (cardiometabolic) and H5 (immune-related) substrates — directly informs Q-IBC-8 (H4 vs H5 vs H5b cohort overlap question) and provides empirical anchor for the project's multi-chain stratification framework.

Claims as triples

• fibromyalgia — coaggregates_with → autoimmune_disease [evidence: Lifelines λR 1.06-1.24, n=166,774; confidence: emerging]
• fibromyalgia — coaggregates_with → atopy [evidence: same study; confidence: emerging]
• fibromyalgia — coaggregates_with → metabolic_syndrome [evidence: same study (FM-cardiometabolic λR 1.00-1.23); confidence: emerging]
• fibromyalgia — coaggregates_with → me_cfs [evidence: shared familial correlation pattern; confidence: emerging]
• fibromyalgia — coaggregates_with → major_depressive_disorder [evidence: shared familial correlation pattern; confidence: emerging]
• familial_aggregation — supports → multi_chain_stratification [evidence: rf range 0.12-0.44 across H4-H5 substrate categories; confidence: emerging]

Methods note

Cross-generational Dutch population cohort (Lifelines). Recurrence risk ratios + familial correlations computed from relatives' disease status. The composite "immune-related disease" includes both autoimmune disease and atopy — somewhat coarse but tractable for cohort-scale analysis. The composite "cardiometabolic" includes obesity, MASLD, T2DM, hypertension, CVD. Cross-sectional disease assessment; longitudinal trajectory not analyzed. Self-reported diagnosis for some categories.

Limitations

• Self-reported diagnosis dilutes precision
• Composite categories (immune-related, cardiometabolic) — relevant for project-internal H4 (cardiometabolic) and H5 (immune-related) framing but doesn't resolve specific celiac/T1DM enrichment
• Dutch population, generalizability question
• Coaggregation ≠ shared causation — could be ascertainment-correlated comorbidity, shared environment, or shared genetic risk
• The familial correlation magnitude (0.12-0.44) is modest — substantial familial sharing exists but is not exclusive (most FM patients won't have affected first-degree relatives across all categories)

Open questions raised

• Q-IBC-21 (new): Are the FM patients with familial autoimmune-disease history more likely to be FM-IgG-positive? The Steen 2025 data establishes the familial-aggregation pattern at population level; within-FM stratification testing within Lifelines or another biobank with FM-IgG measurement would refine to H5-direct.
• Q-IBC-22 (new): Does the FM-cardiometabolic familial correlation (rf for FM-cardiometabolic subset) differ from the FM-immune-related familial correlation (rf for FM-immune subset)? If they overlap, H4 and H5 patient populations may be the same; if separable, H4 and H5 identify distinct family-clustering subgroups.
• Q-IBC-23 (new): Replication in another large biobank (UK Biobank, FinnGen) would substantially strengthen the familial-coaggregation finding.

Triangulation notes

• First population-scale anchor for H4/H5/B-IM-1 framing: H4 (immuno-metabolic) and H5 (autoimmune-genetic-risk) were project-internal chain candidates. Steen 2025 supplies population-scale familial-coaggregation evidence that supports BOTH chain candidates as predicting familial-correlation patterns in FM.
• Informs Q-IBC-8 directly: the H4-vs-H5 cohort-overlap question was the operational decision point. Steen 2025 shows FM coaggregates with BOTH cardiometabolic AND immune-related disease in families — consistent with EITHER (a) one underlying genetic substrate driving both family clusters, OR (b) FM being a mosaic of H4-dominant and H5-dominant subgroups in different families. Within-FM stratification (Q-IBC-21) would resolve.
• Supports the FM-MetS framing of H4: the rf 0.12-0.44 familial correlations between FM and cardiometabolic disease are non-trivial — predict that FM-MetS-comorbid patients enrich in families with cardiometabolic disease beyond population baseline. H4 chain candidate gains population-scale validation.
• Compatible with the celiac/IBS familial pattern in B-Gen-2: IBS familial-coaggregation pattern in Steen 2025 is "more variable" than FM/ME/CFS, consistent with IBS being heterogeneous (covers H5b-NCWS subset + non-NCWS subset).

Bridges

• B-IM-1 + B-Gen-1 + B-Gen-2 + B-Gen-3 partial closure at familial-aggregation level: all four H4/H5/H5b bridges gain population-scale familial-aggregation evidence consistent with their chain claims. Closure at family-aggregation level doesn't substitute for FM-direct evidence (still needed) but validates that the chain claims are not refuted by population-scale data.

Ontology additions needed

• Consider adding familial_aggregation as composite-process entity (analytical framework)
• Consider adding recurrence_risk_ratio as methodology entity
• Confirm atopy is in ontology

Chain-map update

• Multi-chain framework validation: the project's H1 + H2 + H3 + H4 + H5 + H5b stratification framework is consistent with population-scale familial-aggregation evidence showing FM clusters with both immune-related (H1/H2/H5/H5b) and cardiometabolic (H4) family patterns.
• Q-IBC-8 direction-decision data: gains substantial empirical anchor. Direction-decision still pending within-FM stratification, but the population-level framing is now empirically grounded.

Confidence-tier framing

• FM coaggregates with immune-related disease in families: emerging (Lifelines n=166,774, λR 1.06-1.24)
• FM coaggregates with cardiometabolic disease in families: emerging (λR 1.00-1.23)
• ME/CFS-FM-MDD share familial correlation pattern: emerging (rf 0.12-0.44)
• Familial aggregation as evidence of shared genetic / environmental risk: inferred (population-cohort framework consensus)
• H4-H5 patient-cohort overlap pattern: bridging (population-level supports either of two interpretations; within-FM stratification pending)