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

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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]
 
IMG_0106.png
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.

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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.

IMG_0108.png
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.

IMG_0109.png
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
 
abstract said:
Of the FDs, ME/CFS is most closely related to IDs.
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Some days, this stuff really grinds me down. This is one of those days. 'Related to'? rather than correlated with? that makes it sounds as though ME/CFS is a type of depression or anxiety disorder.

Studying genetic liability shared with related disorders can provide further insight into the genetics of FDs.

Due to their high comorbidity with FDs, internalizing disorders (IDs) are good candidates to study alongside FDs. For instance, individuals who meet diagnostic criteria for ME/CFS, IBS, or FM show higher rates of major depressive disorder (MDD) (odds ratios [ORs] = 3.87–12.62) and generalized anxiety disorder (GAD) (ORs = 3.19–9.81) than those who do not meet FD diagnostic criteria (Thomas et al., Reference Thomas, Gillespie, Kendler, Oldehinkel, Rosmalen and van Loo2024).
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Here are some ideas why there might be a relationship between ME/CFS in a person and an "internalising disorder" in a relative:

* We know that someone with ME/CFS can get diagnosed with depression and anxiety disorder, because the survey tools for the mood disorders ask about fatigue and not being able to do what was done before, because some doctors think they are the same thing, and because having ME/CFS is not fun. This study also shows that someone diagnosed with ME/CFS is more likely to have a family member diagnosed with ME/CFS. That family member with ME/CFS is therefore also likely to be diagnosed with depression and/or anxiety.

* People with ME/CFS tend to live a certain sort of constrained low-energy life. So do some people with depression (who may have various sorts of diseases that depression is a symptom or result of). It's not surprising that a person with ME/CFS might find a person with depression is an understanding and compatible person to partner with.

* Caring for a person with ME/CFS can be hard and isolating, and the onset of ME/CFS affects the hopes and dreams of the couple. It is not surprising that the spouse of a person with ME/CFS is more likely to be depressed and anxious.


The observed familial coaggregation and familial correlations between FDs and IDs suggest shared etiological mechanisms between these groups of disorders.
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Well yes, if you use a definition of depression that involves fatigue and an inability to do the things that used to give you pleasure, I guess depression and ME/CFS do have a shared etiology...

I think a big part of the problem is that "depression" can be a symptom and a consequence of a lot of things.

For instance, emotion regulation problems have been linked to IDs, ME/CFS, and FM (Bram, Gottschalk, & Leeds, Reference Bram, Gottschalk and Leeds2018; Picó-Pérez et al., Reference Picó-Pérez, Radua, Steward, Menchón and Soriano-Mas2017; Pinto et al., Reference Pinto, Geenen, Wager, Lumley, Häuser, Kosek and da Silva2023), while inflammation has been associated with FDs and MDD (Andrés-Rodríguez et al., Reference Andrés-Rodríguez, Borràs, Feliu-Soler, Pérez-Aranda, Angarita-Osorio, Moreno-Peral and Luciano2020; Burns et al., Reference Burns, Carroll, Mathe, Horvat, Foster, Walker and Keely2019; Harsanyi, Kupcova, Danisovic, & Klein, Reference Harsanyi, Kupcova, Danisovic and Klein2023; Strawbridge, Sartor, Scott, & Cleare, Reference Strawbridge, Sartor, Scott and Cleare2019).
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Ugh.
 
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.
 
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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.
We use the terms familiality and familial correlation rather than heritability and genetic correlation because our methods do not disentangle genetic from shared environmental effects. However, evidence suggests that for most disorders, familial aggregation results from genetic factors, with limited impact from shared environmental factors.
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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.
 
ME/CFS Skeptic said:
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.
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The supplementary material states:

In the second and third assessment of Lifelines, chronic fatigue syndrome (ME/CFS), fibromyalgia (FM) and irritable bowel syndrome (IBS) were assessed to official diagnostic criteria. Supplementary Table 1 of previous work describes in detail how these official diagnostic criteria were applied in Lifelines (van Loo, Maeder, Bos, & Rosmalen, Manuscript under review).
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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.
 
ME/CFS Skeptic said:
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.
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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.
 
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.
 
Yann04 said:
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.
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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.
 
jnmaciuch said:
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.
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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)
 
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