Familial coaggregation and shared familiality of functional and internalizing disorders in the Lifelines cohort, 2025, Bos et al

Familial coaggregation and shared familiality of functional and internalizing disorders in the Lifelines cohort

Martje Bos, Rei Monden, Naomi R. Wray, Yiling Zhou, Kenneth S. Kendler, Judith G. M. Rosmalen, Hanna M. van Loo, Harold Snieder

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Background
Functional disorders (FDs) are characterized by persistent somatic symptoms and are highly comorbid with internalizing disorders (IDs). To provide much-needed insight into FD etiology, we evaluated FD and ID familial coaggregation and shared familiality.

Methods
Lifelines is a three-generation cohort study, which assessed three FDs (myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS], irritable bowel syndrome [IBS], and fibromyalgia [FM]) and six IDs (major depressive disorder [MDD], dysthymia [DYS], generalized anxiety disorder [GAD], agoraphobia [AGPH], social phobia [SPH], and panic disorder [PD]) according to diagnostic criteria.

Based on 153,803 individuals, including 90,397 with a first-degree relative in Lifelines, we calculated recurrence risk ratios (λRs) and tetrachoric correlations to evaluate familial aggregation and coaggregation of these disorders in first-degree relatives. We then estimated their familiality and familial correlations.

Results
Familial aggregation was observed across disorders, with λR ranging from 1.45 to 2.23 within disorders and from 1.17 to 1.94 across disorders.

Familiality estimates ranged from 22% (95% confidence interval [CI]: 16–29) for IBS to 42% (95% CI: 33–50) for ME/CFS.

Familial correlations ranged from +0.37 (95% CI: 0.24–0.51) between FM and AGPH to +0.97 (95% CI: 0.80–1) between ME/CFS and FM.

The highest familial correlation between an ID and FD was +0.83 (95% CI: 0.66–0.99) for MDD and ME/CFS.

Conclusions
There is a clear familial component to FDs, which is partially shared with IDs. This suggests that IDs and FDs share both genetic and family-environmental risk factors. Of the FDs, ME/CFS is most closely related to IDs.

Link | PDF (Psychological Medicine) [Open Access]

 

Can you add the tag «lifelines» please?

 

Sure, I added "lifelines study" since that's the tag used by other threads.

 

Figure 1. Familial coaggregation of internalizing and functional disorders amongst first-degree relatives expressed in λR. Note:FDR, first-degree relative; MDD, major depressive disorder; DYS, dysthymia; GAD, generalized anxiety disorder; AGPH, agoraphobia; SPH, social phobia; PD, panic disorder; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; IBS, irritable bowel syndrome; FM, fibromyalgia; λR, recurrence risk ratios. λR adjusted for age, age2, sex, and number of relatives present in the data. Estimates in bold are significant at p < .01. For 95% confidence intervals, see Supplementary Table 1.


Figure 2. Tetrachoric correlations between internalizing and functional disorders, for (a) siblings and (b) parent-offspring pairs/trios. Note: MDD, major depressive disorder; DYS, dysthymia; GAD, generalized anxiety disorder; AGPH, agoraphobia; SPH, social phobia; PD, panic disorder; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; IBS, irritable bowel syndrome; FM, fibromyalgia; rtet, tetrachoric correlation. Estimates in bold are significant at p < .01. For 95% confidence intervals, see Supplementary Tables 2 & 3.


Figure 3. Familial coaggregation of internalizing and functional disorders amongst spouses, expressed in λR. Note: MDD, major depressive disorder; DYS, dysthymia; GAD, generalized anxiety disorder; AGPH, agoraphobia; SPH, social phobia; PD, panic disorder; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; IBS, irritable bowel syndrome; FM, fibromyalgia; λR, recurrence risk ratio. λR adjusted for age, age2, sex, and presence of spouse in the data. Estimates in bold are significant at p < .01. For 95% confidence intervals, see Supplementary Table 1.


Figure 4 (a) Familiality and (b) familial correlation estimates of internalizing and functional disorders based on both first- and second-degree relatives. Note: MDD, major depressive disorder; DYS, dysthymia; GAD, generalized anxiety disorder; AGPH, agoraphobia; SPH, social phobia; PD, panic disorder; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; IBS, irritable bowel syndrome; FM, fibromyalgia; rf, familial correlation. See Supplementary Table 4 for familiality estimates for first- and second-degree relatives separately and Supplementary Table 5for 95% confidence intervals of familial correlation estimates

 

How can they know that A increases the risk of B when all they have is correlation?

 

Others have already described how messy the Lifelines cohort is, I wouldn't be suprised if this is a matter of:
Oats are related to milk and blueberries but not wheat as those are often found together in my morning porridge.

 

They said they evaluated the Fukuda criteria yet 4.7% of the more than 150.000 people in the cohort had ME/CFS (Table 1)? That seems an unreasonably high estimate.

 

If I understand the data correctly, having one (or more) first-degree relatives with ME/CFS makes it 2.23 times more likely that you have ME/CFS compared to the general population (which includes those with first-degree relatives with ME/CFS).

 

The authors clarify that they could not distinguish between genetics and shared environments.

For most disorders the recurrence risk ratio was similar for first or second degree relatives and the authors argue that this suggests that the recurrent was likely not due to a shared environment. ME/CFS was an exception however, as the recurrence risk ratio dropped from 2.23 to only 1.17 for second degree relatives.

 

The supplementary material states:

So I suppose we have to wait until that other manuscript is published until we know more how the Fukuda criteria were assessed (my guess is through questionnaires rather than a medical examination). The paper itself does not comment on the remarkable high prevalence for ME/CFS as far as I can tell.

 

Unreasonably high? I would go even further than that. I live in the Lifelines area.
GP's and specialists don't "do" ME/CFS, not even the specialist chronic fatigue.
The physical exam I got there was specialist and assistant taking one side each. Heart lungs and lymph. Rush job.
It took me longer to get undressed and get dressed again.
So how would a patient get a diagnose ME/CFS?
It would be CFS maybe, or FND,FSS or whatever. Not ME/CFS.

 

@ME/CFS Skeptic there’s also a graph on spouses (figure 3). It has ME/CFS at a λR of 2.01.

 

unfortunately might not tell us much (via environment vs genetics) because pwME may be far more likely to date other pwME.

 

Absolutely. It really only highlights how many confounders there are in this data, and how little value it has.

 

The idea of a genetic link really does resonate with me though. My mum has an ME/CFS like chronic illness that looks similar to mine when I was really mild (she gets a migraine and has to lay in bed for days after she does too much) although she was diagnosed with hEDS (after lots of "depression" and "burnout" type misdiagnoses) and thats the label she preferred.

And basically my mums side of the family every one has one sort of autoimmune or autoinflammatory disease.

But that could all be random chance of course. But it definitely feels like theres something weird going on with our genetics messing up our immune systems.

 

Anecdotally I know several people (including myself) who have a family history of Hashimoto’s and ended up with ME/CFS. Not everyone with Hashimoto’s in the family ends up with ME/CFS, but it seems more likely that at least one person will.

I keep coming back to a “perfect storm” idea of ME/CFS—there could be a wide variety of genetic predispositions which don’t guarantee ME/CFS but make you a lot more likely to develop it if you also have the right combination of environmental triggers. You just keep stacking cards towards one “broken loop” that tips over when you get a viral infection or something else as the precipitating event.

My guess is that sex hormone fluctuations would be one common element of the “perfect storm”, given the higher frequency of women receiving the diagnosis, but it would not be required.

 

So it's become a thing now, that the grifters just gift themselves a huge number of useless academic citations? This is all similar to the awful DanFunD stuff. All useless research, but they generate a dozen or so papers out of it. All saying nothing, just fishing expeditions with no aim other than propping up their ideology and the business it creates.

Literally none of this has any scientific merit, because everything that goes in the black box they made up was arbitrarily labeled. So as usual they are 'exploring' their own thoughts and beliefs just to make the same spurious assertions that they still can't back up with anything more than "we've put this stuff we can't tell apart into a bag, and best we can tell is they're in the bag".

It's getting to the point where some astrological cults were more serious about their work. Really.

 

What’s striking in my case is of my direct “ancestors”, (people who contributed genetically to me), its only the women who had autoimmune/autoinflammatory/(ME/CFS, Migraine like illnesses). Literally only the women. It’s my mum’s family. My mum’s mum’s family, and my mum’s mum’s mum’s family.
(I’m a man tho and the only one with a “severe” disability)