REVIEWS

Family history of rheumatoid arthritis:

an old concept with new developments
Thomas Frisell1, Saedis Saevarsdottir2,3 and Johan Askling1,3
Abstract | Family history of rheumatoid arthritis (RA) is a proxy for an individual’s genetic and, in
part, environmental risk of developing RA, and is a well-recognized predictor of disease onset.
Although family history of RA is an old concept, the degree of familial aggregation of RA, whether
it differs by age, sex, or serology, and what value it has for clinical decisions once a diagnosis of RA
has been made remain unclear. New data have been emerging in parallel to substantial progress
made in genetic association studies. In this Review, we describe the various ways that familial
aggregation has been measured, and how the findings from these studies, whether they are
based on twins, cohorts of first-degree relatives, or genetic data, correspond to each other and
aid understanding of the aetiology of RA. In addition, we review the potential usefulness of family
history of RA from a clinical point of view, demonstrating that, in the era of big data and genomics,
family history still has a role in directing clinical decision-making and research.

1
Clinical Epidemiology Unit,
Department of Medicine
Solna, Karolinska Institutet,
T2 Karolinska University
Hospital, SE‑171 76
Stockholm, Sweden.
2
Institute of Environmental
Medicine, Karolinska
Institutet, BOX 210, SE‑171
77 Stockholm, Sweden.
3
Rheumatology Unit,
Department of Medicine
Solna, Karolinska Institutet,
Karolinska University
Hospital, SE‑171 76
Stockholm, Sweden.
Correspondence to J.A.
johan.askling@ki.se
doi:10.1038/nrrheum.2016.52
Published online 21 Apr 2016
Rheumatoid arthritis (RA) clusters in families, mean‑
ing that relatives of patients with RA are at increased
risk of developing the disease. Indeed, family history
has long been recognized as one of the strongest risk
factors for developing RA1,2 and, as such, it is routinely
assessed as part of the clinical work‑up of individuals
with inflammatory arthritis.
The study of familial aggregation of disease is moti‑
vated by potential clinical usefulness and by the con‑
cern of patients, who worry about what risks they might
have inherited or could be passing on to the next gen‑
eration in terms of developing RA, the clinical course
and treatment. Accurate estimation of the strength and
characteristics of familial aggregation is difficult. Ideally,
it requires large, representative populations of families
with valid diagnoses of RA. Data based on registries and
total-population studies are providing increasingly pre‑
cise calculations of the predictive value of family history
of RA for disease onset.
Familial clustering is caused by genetic and environ‑
mental factors shared within families, and, therefore, its
magnitude and pattern of distribution provides infor‑
mation on the aetiology of RA. In particular, observed
familial risks can be used to estimate the heritability of
RA, which is essential to contextualize other aetiological
studies, especially genetic studies. Several studies have
also addressed the usefulness of family history in the
clinic, with the hypothesis that such information might
predict clinical course and prognosis if familial factors
influencing disease onset also influence disease severity,
or to test if treatment response is itself hereditary.
In this Review we provide an overview of the his‑
tory and the current state of research on the familial
aggregation of RA, including the different study designs
and metrics used in this field (BOX 1; FIGS 1,2), and dis‑
cuss what can be learned about the disease. We also
explore whether this information might have value in
the clinical setting.
Familial risk of RA
A brief historical overview
Although a heritable component to RA was suspected as
early as 1810 (REF. 2), collection of data sets of sufficient
quality to prove the presence of familial aggregation, let
alone to calculate precisely its magnitude and character‑
istics, has proven difficult. Inspired by early case reports
of familial disease1–3, several studies in the 1950s com‑
pared self-reported family history of RA among clini­cally
verified cases with that among control subjects. Cases
reported two to six times higher prevalence of RA in their
first-degree relatives (FDRs)4–6. One estimate suggested
that risk was raised by as much as 15-fold7. Self-reported
family history, however, is recognized as being likely to
result in substantial misclassification unless diagnosis in
relatives can be verified5. Self-reporting might also lead to
overestimation, for example if patients with RA are more
aware of the disease history of relatives with RA than are
control individuals.
To overcome these limitations, several ambitious
projects in the late 1950s and the 1960s involved clini‑
cal examinations of hundreds of relatives of individuals
with RA and of matched controls. The results largely

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Key points Over the following decades, several influential stud‑

• Family history of rheumatoid arthritis (RA) is one of the strongest known risk factors
for developing RA, conferring twofold to fourfold increased risk in
first-degree relatives
• The heritability of RA seems to be ~40%, and is higher for seropositive than for
seronegative RA
• Familial risk does not differ by sex, which suggests that genetic effects do not explain
why RA is more common in women than men
• Family history remains a strong independent predictor of RA onset, despite advances
made in identifying genetic risk alleles during the past decade
• Data so far suggest familial aggregation for treatment response but not for
clinical characteristics
corroborated the earlier findings2,8–10. Critics, however,
claimed that the studies used unrepresentative samples
and non-validated definitions of RA11. In particular, the
lack of association reported in total-population sur‑
veys performed in Native American populations12–15
was interpreted as evidence for bias in earlier studies.
If some weak familial aggregation of RA did exist, it
was argued at the time, it did not fit a simple Mendelian
inheritance pattern, making heritable factors unlikely
to be important for RA 10–12. Total-population sur‑
veys did have the advantage of avoiding the potential
selection bias of hospital-based surveys, but the low
prevalence of RA resulted in low power, and the lack
of statistical significance was interpreted as absence of
familial aggregation12,16.
Box 1 | Measurement of familial aggregation
The translation between measures of familial clustering is dependent on disease
prevalence. The two most common methods to measure clustering use relative risks:
Risk in relative of affected individual
λ=
Risk in the general population
and
NatureRisk
Reviews | Rheumatology
in relative of affected individual
Familial risk =
Risk in relative of unaffected individual
The λ, a traditional measure, only requires background data on disease incidence.
NatureorReviews
The use of ordinary case–control | Rheumatology
cohort designs, yielding familial relative risks, has
become more common. Each pair of relatives can be analysed separately or exposure
can be defined as any affected first-degree relative. If family size does not depend on
disease status, with these two definitions the familial risk will be roughly equal.
Twin studies often estimate concordance rates. Probandwise concordance is the
proportion of affected twins whose co‑twins are also affected, and pairwise
concordance is the proportion of all twin pairs where both twins are affected.
The probandwise rate is the numerator of the λ, and might, for example, be compared
with the expected population risk. The pairwise rate is difficult to compare to any other
rate, and its use is discouraged94. The sample concordance will differ from the
population concordance unless affected twins were independently and completely
ascertained, although ascertainment correction is possible42,43,94.
The same familial risk would imply stronger familial aggregation for a common than
for a rare disease. Thus, an alternative metric is the tetrachoric correlation, which is the
correlation in relatives’ liability to develop RA under the liability-threshold model.
These correlations are directly related to heritability, and for a given disease prevalence
heritability gives a specific familial risk, although other factors shared by relatives might
increase familial risk further.
ies demonstrated higher RA concordance in monozy‑
gotic than in dizygotic twins17–19. Together with the
accumulating evidence for a substantial contribution
of the HLA region to the risk of RA20, the findings in
twins settled the point of whether RA clustered in fam‑
ilies, but left unanswered the question of the strength of
aggregation. In the early 1990s, opinions on the impor‑
tance of familial aggregation of RA ranged from it being
very weak21 to it being one the strongest risk factors for
RA22. This issue was not resolved in contemporary stud‑
ies. Several small studies reported high rates of RA in
relatives of index patients but did not include compari‑
son groups23–25. Two prospective cohort studies in rela‑
tives of patients treated at RA clinics found that risk was
only roughly doubled in FDRs26,27. A case–control study
reported about a fourfold increase in risk28, but the
power was limited and the generalizability questionable.
Registries and total-population studies
To avoid potentially problematic selection bias in
hospital-based populations but to retain sufficient sta‑
tistical precision, complete records of RA and familial
relationships in large unselected populations are needed.
Several countries have national registries, which have been
used for studies of familial aggregation (TABLE 1). Although
few in number, these studies have been important for
resolving several issues about familial clustering.
One study used complete pedigrees of about 270,000
living Icelanders29, obtained from a data set established as
part of the deCODE project30. The study identified more
than 1,000 living patients with RA and found signifi­
cant familial aggregation of RA in FDRs (λ ~4) and
second-degree relatives (λ ~2); definitions of λ are pro‑
vided in BOX 1 and FIGURE 1. Of note, the study was esti‑
mated to cover ~60% of all patients with RA in Iceland,
and attendance at the participating rheumatologists’
clinics might itself have been familial.
Hemminki et al.31 identified almost 50,000 Swedish
patients hospitalized for RA up to 2004. They analysed
data in national registries of hospitalizations and famil‑
ial relationships, and found familial risks (standardized
incidence ratios) of 3.0 in parents and 4.6 in siblings.
In Denmark, the risk for RA among parents of ~9,000
RA patients was compared with that in parents of more
than 3,000,000 RA‑free individuals, yielding hazard ratios
of 2.6–2.9 (REF. 32).
A comprehensive analysis of the national Swedish
registries, with longer follow‑up than the other registry
studies, and, importantly, including patients receiving
non-primary outpatient care, identified about 90,000
patients with RA33. Familial risks were in line with the
previous total-population estimates, with an odds ratio
of 3.2 (95% CI 3.0–3.3) for FDRs and of 1.9 (1.7–2.2)
for second-degree relatives. Of note, the estimates
remained similar when restricting analysis to the ~12,000
patients with recent-onset RA in the clinical Swedish
Rheumatology Quality of Care Register and ~2,800 in
the EIRA case–control study (http://www.eirasweden.se/
index1.htm)33, where the validity of diagnosis and serology
was better substantiated than in the full Swedish register.

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16 0.6 Since familial clustering might also be expected to arise

λ, FDR from shared non-genetic factors, upper limits to her‑
Familial risk, FDR 0.5 itability of RA were set in these studies. Attempts have
Tetrachoric correlation
8 also been made to tease apart genetic and non-genetic

Tetrachoric correlation
0.4 familial factors.
Relative risk

4 0.3
0.2
2
0.1
1 0
0 10 20 30 40 50 60 70 80 90 100
Heritability (%)
Figure 1 | Inter-relations of familial risk measures. Assuming a disease prevalence
of 1%, the λ and the familial risk are virtually inseparable,Nature
whereas the tetrachoric
Reviews | Rheumatology
correlation is always half the heritability and is unaffected by prevalence. If factors other
than additive genetics contribute to familial clustering, all measures would be increased
further. Conversely, if familial risk measures are used to estimate heritability in the
presence of shared environmental or non-additive genetic effects, heritability will be
overestimated. FDR, first-degree relative.
Several early studies speculated that the familial
aggregation was modified by sex or age at onset, but
results were inconclusive23,28,34–36. The registry-based
studies ruled out any sex difference in familial risk31–33,
which is interesting given the marked female predom‑
inance of RA, but show that early age at onset confers
increased familial risk33. This finding might reconcile
some of the differences observed between studies and
types of relatives37.
Overall, the risk of RA in FDRs of affected individu‑
als is increased roughly threefold, and in second-degree
relatives approximately twofold, with the association
being modified by age at onset but not by sex. The
largest total-population surveys so far have all been
Scandinavian and analyses in other ethnic groups would
be valuable.
Heritability of RA
The driving force behind most studies of the familial
aggregation of RA, rather than being to improve predic‑
tion of disease onset, has been interest in how impor‑
tant genetic factors are in the development of RA. The
role of genetic factors is often quantified as heritability,
that is, the proportion of liability to develop a disease
that is due to genetic factors (BOX 2). Heritability esti‑
mates are inherently based on several assumptions, and
the method used should be taken into account when
interpreting the values reported for RA (TABLE 2).
The first heritability estimates for RA, reported by
Lawrence in 1970 (REF. 2), were 60–70% for seropositive
RA. The sample, however, was not well described and
estimates were based on the assumption that familial
aggregation was due entirely to additive genetic effects38.
Under the same assumption, we used data for FDRs in
the Swedish Multigeneration Register and the Swedish
Patient Register and estimated that heritability was 40%33.
Twin studies
The classic method of separating nature from nurture
is to contrast familial risks between relatives who have
different degrees of genetic and environmental relation‑
ships, such as adoptees and twins. Twins are particularly
useful, since, under some assumptions39, the difference
in correlation between monozygotic and dizygotic twins
would be directly proportional to the heritability.
In what is perhaps the most influential study of famil‑
ial aggregation in RA, MacGregor and colleagues40 used
data from two previously published twin studies to esti‑
mate heritability. The first of these had studied same-sex
Finnish twins with RA, identified through the national
Sickness Insurance Register 17, and reported pairwise
concordance rates of 12% in monozygotic and 3% in
dizygotic pairs (BOX 1). The second study had recruited
203 affected twin pairs through participating rheumatol‑
ogists and a media campaign in the UK, and reported a
probandwise concordance rate of 15% in monozygotic
and 4% in dizygotic twin pairs18. MacGregor et al. esti‑
mated the heritability to be 65% in the Finnish study
group and 53% in the UK sample. At the time, many
researchers (including those of the two twin studies) had
interpreted the familial risks of 2–5 and the probandwise
concordance rates in monozygotic twins of 15–20% to be
evidence for a weak effect of genes17,18,21. On the herita‑
bility scale, however, it became clear that these data were
actually consistent with a substantial genetic influence.
However, MacGregor and colleagues did not separate
shared genetic and environmental factors, since models
explicitly assumed that twin correlation was due com‑
pletely to additive genetics. Despite the analysis being
done after finding that the effect of shared environment
was not significantly different from zero, power for this
test was very low 40. Unfortunately, low power is seen in
all twin studies of RA. Thus, although assessment of
these populations could in theory shed light on the rela‑
tive importance of genetic versus shared environmental
factors in RA, the scarcity of suitable participants has
so far made these studies noninformative on this point.
Two other twin studies presented concordance rates
consistent with substantial heritability and limited (or no)
influence of shared environment, but low power made
them inconclusive19,41. By contrast, nationwide Danish
studies have reported low monozygotic twin concord‑
ance and low heritability 42 but substantial influence of
shared environment 43, and have concluded that genes
seem less important than other factors for the develop‑
ment of RA. Of note, though, the confidence limits were
broad and, therefore, the apparent discrepancy might be
due to chance variation across studies44,45 (TABLE 2).
The most precise estimate of the heritability of RA
comes from a large study in FDRs rather than twins,
but could be an overestimate if family environment
contributes to the risk of RA. Yet, although the roles of

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A good illustration is the weak contribution of the

FDR, prevalence 0.5% shared epitope alleles, which, despite high prevalence,
128
MZ, prevalence 0.5%
strong effect on RA, and obvious familial aggregation,
FDR, prevalence 1%
64
MZ, prevalence 1% has been algebraically shown to yield a familial risk of
FDR, prevalence 2% about 1.2 (REF. 27). For shared environment to explain
32
Relative risk

MZ, prevalence 2% any substantial part of familial aggregation, an unknown

16
8 the case for genetic risk factors52,53. A special case of a
4
2 RA. This pattern would seem likely, but since the familial
1 nosed severe RA, such factors cannot explain more than
0 10 20 30 40 50 60 70 80 90
Heritability (%)
Figure 2 | Familial risk as a function of heritability and prevalence. The relative
risk of developing rheumatoid arthritis (RA) in first degree relatives (FDRs) and
Nature Reviews | Rheumatology
monozygotic twins (MZ) of patients with RA, compared with that in relatives of non‑RA
controls, as a function of the heritability is shown. For a given disease prevalence, the
heritability gives a specific familial risk. The range should cover plausible values for RA,
and in most populations is 0.5–1.0%. Although the translation between heritability and
familial risk is dependent on prevalence, the dependence is slight for FDRs at moderate
levels of heritability.
several environmental risk factors have been confirmed,
including smoking 46 and alcohol use47,48, some evidence
suggests that any overestimation would be limited.
Nature, not nurture?
Although familial clustering might seem to be expected
from shared environmental factors, a study that com‑
bined information on family history with established
environmental and genetic RA risk factors showed no
part of the familial aggregation was explained by various
non-genetic risk factors. By contrast, the shared epitope
and 76 single-nucleotide polymorphisms explained
about 20% of the familial risk49. These findings might
seem surprising, but are in line with the general find‑
ing from twin studies that shared family environment
is of negligible importance for most studied diseases50.
Indeed, an individual risk factor would need an extreme
association with RA and extreme familial aggregation to
yield more than a modest effect on familial aggregation51.
factor of extremely strong influence or a multitude of
factors of weaker importance would be required, as is
non-genetic factor would be if patients with mild RA
were diagnosed more often if they had a family history of
risk remains at least equally strong for more easily diag‑
100
a small part of the familial aggregation.
Methods to directly estimate heritability through
measurement of genetic relatedness, estimated from
genome-wide genetic markers, have developed rapidly 54.
In contrast to estimates based on family history, which,
as described earlier, might overestimate heritability,
genome-based methods underestimate it because they
can only estimate the proportion tagged by the meas‑
ured markers and miss effects from rare and non-tagged
variants. The latter estimates should be free from envi‑
ronmental and non-additive influences, however, and
the comparison with pedigree-based estimates should
be instructive. Estimates so far have varied considerably,
however. For instance those from Stahl and colleagues53
of 45% are close to pedigree-based heritability, whereas
Lee et al.55 calculated heritability of anti-citrullinated pep‑
tide antibody (ACPA)-positive RA to be 19% (TABLE 2).
Clearly, the latter estimate is lower than most of those
from FDR and twin studies, which, if this estimate is
correct, suggests there must be plenty of rare variants,
non-additive genetic effects, or shared environmental
influences on RA to explain the difference to heritability
estimated from familial aggregation.
Seropositive RA
Two-thirds of patients with RA are seropositive for rheu‑
matoid factor (RF) or ACPAs. Recent genetic studies have
shown differences and similarities in the genetic risk
factors for patients with seropositive and seronegative
RA52,56,57, which supports the view that these phenotypes

Table 1 | Total-population studies of familial aggregation of rheumatoid arthritis

Authors Country Ascertainment of RA Number Estimate (95% CI)
of patients
Grant et al., Iceland Patients attending an RA 1,412 λ for siblings 4.4 (3.3–5.7), for
2001 (REF. 29) outpatient clinic, covering about parents 3.9 (2.6–5.5) and for offspring
60% of all RA patients in Iceland 2.8 (1.6–4.2)*
Hemminki et al., Sweden Hospitalized patients 47,361 IRR for siblings 4.6 (3.0–7.2) and for
2009 (REF. 31) parents 3.0 (2.8–3.2)
Somers et al., Denmark Hospitalizations and 9,118 HR for mother–daughter 2.7 (2.4–3.1)
2013 (REF. 32) outpatient visits and for father–son 2.9 (2.2–3.8)
Frisell et al., Sweden Hospitalizations and 90,372 OR for FDRs 3.2 (3.0–3.3), for siblings
2013 (REF. 33) outpatient visits 3.6 (3.1–4.0), for parents 3.1 (2.9–3.3)
and for offspring 3.2 (3.0–3.5)
FDR, first-degree relative; HR, hazard ratio; IRR, incidence rate ratio; OR, odds ratio; RA, rheumatoid arthritis. *λ denotes risk of
disease for a type of relative to an affected individuals divided by the risk in the general population.

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Box 2 | Heritability 3.95 [95% CI 3.72–4.19] in FDRs) compared with that

Heritability of a trait is defined as the proportion of its variance attributable to additive
genetic effects (that is, the sum of the individual average effects of all alleles across the
genome). Heritability is sometimes referred to as narrow-sense heritability to avoid
mistaking it for the larger proportion that is due to all genetic effects (broad-sense
heritability), which would also contain effects due to dominance and interactions
between alleles at different loci. The concept of heritability, although alternatively
named, was introduced by Fisher in 1918 (REFS 95,96), who showed that the expected
correlation between relatives’ phenotypes could be calculated. In reverse, observed
phenotypic correlations between relatives can be used to estimate heritability38,39.
Fisher’s model, which was extended by Falconer38,39, assumes that risk of disease is the
sum of and interactions between genetic and environmental factors. The tetrachoric
correlation between relatives, therefore, would be the sum of contributions from these
components, and the relative importance of genetic and environmental factors
calculated by solving equation systems of relatives with different relatedness.
In practice, simplifications are needed, and heritability is often estimated from twins,
assuming contributions only from additive genetics and shared environmental factors:
• Correlation for monozygotic twins = 1 × heritability + 1 × shared environment
• Correlation for dizygotic twins = 0.5 × heritability + 1 × shared environment
Alternatively, hereditability is estimated from first-degree relatives (FDRs), assuming
only contributions from additive genetics:
• Correlation for FDRs = 0.5 × heritability
Heritability estimates have practical applications in animal breeding, for instance to
identify traits responsive to selection. Heritability is used in humans to try to answer the
question of nature versus nurture or to set an upper limit for how much all risk alleles
explain a given disease, which acts as a benchmark against which to compare currently
identified genes.
are distinct but related. By focusing on genome-wide sig‑
nificant alleles, these studies have limited ability to assess
the magnitude of the difference between phenotypes,
and whether the lower number of associations with sero­
negative RA reflects lower heritability or is merely due to
limited power remains unclear.
Family studies might provide the answer. Studies
published in the 1950s and 1960s consistently reported
a stronger familial aggregation for seropositive than sero­
negative RA2,9,58. Of note, however, these early studies were
performed before the current classification criteria for RA
were established. The seronegative RA group, therefore,
probably contained patients who would now be diagnosed
as having other arthritis-related diseases, which might
have diluted the true familial aggregation. Among later
studies, only a few reported a stronger familial aggregation
for seropositive RA34 and most reported no significant
difference between phenotypes, although power was gen‑
erally limited and point estimates favoured seropositive
RA17,27,28,59–62. A reanalysis of the data from twins reported
by Silman and colleagues18 has been widely referenced as
evidence for equal heritability (~67% in ACPA-positive
and ACPA-negative RA)63,64, but the estimates were
based on only two and zero ACPA-negative concordant
monozygotic and dizygotic pairs, respectively 65. Two
other twin studies have presented estimates separated by
ACPA serostatus, but with too low power for the findings
to be informative41,43. Alternative designs are needed to
explore the role of seropositive RA further.
In an analysis of the data of the Swedish national reg‑
istries and the EIRA case–control study, familial aggrega‑
tion of seropositive RA was clearly increased (odds ratio
for seronegative RA (2.47 [2.24–2.72])33,66. These risks
translate to heritability of 40–50% for seropositive and
20–30% for seronegative RA, and the degree of familial
aggregation overlaps substantially 33,49,66,67. Although the
validity of the serology may be questioned in diagnoses
based purely on registry information, the pattern seemed
to be strengthened when assessed in subsets of patients
with more-robust diagnoses33 and more-contemporary
patients66, and in the EIRA study population, where
all participants had been tested for RF and ACPA49.
Nevertheless, these studies used different samples from
within the same population, and further studies done in
settings outside Sweden would be valuable.
In recent analyses of data from the Nurses’ Health
Study, family history of RA and/or systemic lupus erythe­
matosus was equally associated with seropositive and
seronegative RA, but family history was self-reported,
frequently many years after disease onset. The high prev‑
alence (~30% of RA patients reported a family history of
RA and/or SLE) suggests that recall bias or diagnostic
uncertainty might have affected results68,69. Heritability
estimated from observed genetic relatedness is consistent
with a considerable difference between sero­positive  and
seronegative RA, being 19% for ACPA-positive RA
and zero for ACPA-negative RA55.
Family studies have also addressed the nature of the
genetic overlap between seropositive and seronegative
RA. Part of the difference in heritability is probably caused
by the stronger associations between the HLA region and
seropositive RA than seronegative RA56. Nevertheless,
the strongest known genetic risk factor, the HLA‑DR4
shared epitope, explains only a minor part of the higher
familial risk49, meaning that other factors must also be
involved. The familial co‑aggregation of seropositive and
sero­negative RA is substantial, with family history of one
being a strong predictor of onset of the other and both
having similar familial co‑aggregation with other sys‑
temic inflammatory diseases66. This finding suggests that
the alleles associated with other chronic inflammatory
diseases are prim­arily shared by the RA subsets. Familial
co‑aggregation would also be expected if a proportion of
people with seronegative RA should be classified as sero‑
positive. This likelihood is supported by studies in which
substantial proportions of patients negative for anti-cyclic
citrullinated protein antibodies carried other specific
ACPAs, anti-mutated citrullinated vimentin antibodies,
or anti-carbamylated protein  antibodies70,71.
Missing heritability
Genome-wide association studies in collaborative pro‑
jects that have pooled several large RA cohorts have
identified more than 100 risk loci associated with
RA52,72,73. The proportion of heritability not yet explained
by identified risk alleles is sometimes referred to as the
missing heritability. It provides important contextual‑
ization for further genetic studies of RA, indicating the
amount of genetic effects still to be identified. From
the perspective of familial risk, this quantity is interest‑
ing because it gives an idea of when (or if) family history
could be replaced by genetic factors as predictors of RA.

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Table 2 | Studies estimating the heritability of rheumatoid arthritis

Study Sample Relationship Heritability estimate (95% CI) Main assumptions
Overall Seropositive Seronegative
Lawrence, 1970 Manchester family survey* FDRs — 60% (36–84)‡ — Only additive genetic effects
(REF. 2)
Lawrence, 1970 380 twin pairs from ARC Twins — MZ, 70%§; — Only additive genetic effects
(REF. 2) twin survey DZ, 60%§
MacGregor et al., 27,000 Finnish twins, linked Twins 65% (50–77) — — Only additive genetic
2000 (REF. 40) to sickness insurance register, effects after finding family
from Aho et al.17 environment not significantly
different from zero
MacGregor et al., 203 UK twin pairs recruited Twins 53% (40–65)|| — — Only additive genetic
2000 (REF. 40) through clinics (~33%) and a (proband‑wise effects after finding family
media campaign (~67%), from selection) environment not significantly
Silman et al.18 different from zero
van der Woude 148 UK twin pairs (the subset Twins 66% (44–75)|| 68% (55–79) 66% (21–82) Only additive genetic effects
et al., 2009 from Silman et al.18 with serum
(REF. 65) samples)
Stahl et al., 2012 5,485 patients with RA from Bayesian — 36%¶ — Only additive genetic effects
(REF. 53) Stahl et al.73 and Wellcome polygenic
Trust study98 model
Stahl et al., 2012 5,485 patients with RA from GCTA — 45%¶ — Only additive effects of
(REF. 53) Stahl et al.73 and Wellcome tagged variants
Trust study98
Svendsen et al., 45,000 Danish twins, screened Twins 12% (0–76). — — Only additive genetic
2013 (REF. 43) for RA C: 50% (0–72) effects and shared family
environment
Frisell et al., 2013 90,000 patients with RA from FDRs 41% (39–42)# 45% (42–47)# 28% (23–33)# Only additive genetic effects
(REF. 33) Swedish national registries
Frisell et al., 2013 2,871 Swedish patients with FDRs 37% (32–44)# 52% (42–61)# 21% (0–44)# Only additive genetic effects
(REF. 33) RA from the EIRA study
Haj Hensvold ~7,000 Swedish twins, from RA Twins 39% (0–66), 41% (0–74), — Only additive genetic
et al., 2015 patient registry C: 0 (0–44) C: 2 (0–54) effects and shared family
(REF. 41) environment
Lee et al., 2015 9,638 patients with RA from GCTA — 19.4% –1% (−5 to 5)‡ Only additive effects of
(REF. 55) Stahl et al.73, Okada et al.52, 18–20.8)‡ tagged variants
and ACPA-negative cases
from EIRA study
ACPA, anti-citrullinated protein antibody; C, common family environment; DZ, dizygotic twins; FDR, first-degree relative; GCTA, genome-wide complex trait
analysis; MZ, monozygotic twins. *No further information about this sample is available. ‡Confidence intervals calculated from ±1.96 × SE. §Standard errors not
reported. ||Difference in estimates depend on assumptions about sampling scheme: MacGregor et al. assumed that each pair was recruited through affected index
twin (λMZ = 15) and van der Woude et al. used a model assuming that pairs were symmetrical99, which effectively counts concordant pairs twice (λMZ = 27). ¶Estimate
derived from publication by summing reported estimates for MHC and non-MHC. #CIs not included in original publication.

The proportion of the heritability explained by loci
identified so far has been claimed to be quite high,
~50%64,72,74 or even higher 63 in some reports. However,
these estimates have been based on different measures
of heritability and the degree of how much is explained
by the HLA region has varied73,75–77. In a study that used
molecular data, variants identified in the HLA region
would explain 12.7% of the liability to develop ACPA-
positive RA78, but the proportion was much lower for
ACPA-negative RA. Non-HLA loci explain far less, with
100 explaining only 5.5% of RA heritability in European
populations and 4.7% in an Asian population, although
no reference was made to what value the heritability was
assumed to have52. All identified loci, therefore, seem
to explain <20% of liability for ACPA-positive RA and
<5% for ACPA-negative RA. Thus, compared to the
heritability we have reported of ~50% for ACPA-positive
RA and ~20% for ACPA-negative RA on the basis of
familial aggregation33, the missing heritability would be
at least 50–60% and 65–75%, respectively.
In line with these estimates, a study showed that the
shared epitope and leading single-nucleotide polymor‑
phisms from 76 identified loci only explained about
20% of the familial aggregation for ACPA-positive RA
and virtually nothing for ACPA-negative RA49. Another
study found that self-reported familial RA was associ‑
ated with substantially increased prediction of RA when
added to a model that included a literature-based genetic
risk score for the disease69. These reports suggest that
many alleles remain unidentified, and the predictive
value of the family history of disease is not likely to be
replaced by genotyping any time soon.

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Family history in the clinical setting

Individuals referred to rheumatology clinics are rou‑ General population
FDRs of RA patients Healthy RA
tinely asked about family history of chronic inflam‑
matory diseases as part of the diagnostic work‑up.

Population proportion
This practice seems sensible considering the familial
aggregation of RA, including cross-disease aggregation
with other inflammatory arthritis66, but the usefulness
of such information is not always clear. Of note, the
increased risks described in this Review are related to
the general population, and would probably be quite dif‑
ferent among individuals who present with symptoms of
arthralgia or systemic inflammation. Indeed, some stud‑
ies show that self-reported family history of RA can be
a predictor for not having RA in the clinical setting 79,80,
probably because self-reporting is unreliable and subject
to recall bias. Studies have suggested that the positive
predictive value of self-report is 25–75%, depending
on the phrasing of the question23,59. Familial aggrega‑
tion of RA seems to be mostly specific, although there
is some familial co‑aggregation with connective-tissue
and autoimmune diseases31,66,81 but little to none with
osteoarthritis or unspecified arthralgia66. If family his‑
tory of disease is to help in making a diagnosis, care
must be taken that the individual’s report is as accurate
as possible.
Whether family history of RA is of any value for
clinical care and prediction beyond diagnosis is
unclear. The liability-threshold model (FIG. 3) suggests
that it would be, since patients with RA and a fam‑
ily history of RA would on average have higher lia‑
bility than RA patients without such a family history.
Assuming that the risk of developing RA displays some
correlation with disease activity, we could hypothesize
that patients with familial RA should have more severe
disease, and possibly be more resistant to treatment.
So far, however, there is little evidence to support
this hypothesis.
Disease severity
Early studies generally found increased familial risks
for erosive and active RA2, but since these studies pre‑
dated modern RA classification criteria, the findings
might reflect diagnoses with high specificity rather
than the relevant underlying pathogenic mechanisms.
By contrast, later studies showed, with few exceptions82,
no substantial differences in clinical characteristics
(beyond seropositive status and age at onset) between
familial and sporadic RA34,61,62,67,83–85. Later studies also
demonstrate no familial aggregation of RA disease char‑
acteristics per se86,87, although, again, with the exception
of seropositive status and age at onset 33,88,89 and in one
study rheumatic nodules88, which otherwise would have
been expected if these disease characteristics identified
aetiologically distinct subsets.
Treatment response
Since a substantial proportion of the identified RA risk
loci tag pathways targeted by current therapies or that
are involved in general inflammatory response52, it
seems reasonable that family history of RA might be pre‑
dictive of disease progression and treatment response.
Liability to develop RA
Figure 3 | The liability-threshold model. The distribution
of risk of rheumatoid arthritis (RA) is shown in the general
Nature Reviews | Rheumatology
population and first-degree relatives (FDRs) of patients
with RA according to the standard model of disease
development in quantitative genetics38,97. Under this
model, everyone is assumed to have a value on a liability
continuum related to risk of developing RA, but only those
with values above a certain threshold actually develop the
disease. An individual’s liability is a sum of his or her risk
factors, such as individual risk alleles, and lifestyle factors
like smoking, with each additional risk factors moving the
person closer to the threshold. In populations at increased
risk compared with the general population, the proportion
past the threshold is higher. Heritability estimates
correspond to the proportion of the variance in liability
that is explained by additive genetic effects, where
additive refers to the average effects summing without
interactions on the liability scale.
As with disease severity in general, there is limited evi‑
dence to support such predictive value. In one prospec‑
tive study, family history of RA was linked to increased
risk of radiographic progression90, whereas in another
no association was found61. In one study, while family
history of RA did not predict response to methotrex‑
ate or anti-TNF therapy 67, there was some indication
that 1‑year drug survival in FDRs taking TNF inhib‑
itors was predictive of the patient’s own drug survival
on these drugs67. This finding is tentatively supported
by several genotype-based heritability estimates. In
a small Icelandic study, heritability of joint destruc‑
tion was estimated to be 60%91, and in a Dutch study
the heritability for change in swollen and tender joint
counts in patients taking TNF inhibitors was 60–80%92.
By contrast, a UK study found no significant heritabil‑
ity of response to any TNF inhibitors by any measure,
although point estimates for heritability were possibly
slightly increased in the subset treated with anti-TNF
monoclonal antibodies93. These studies were limited by
low power and need to be replicated, but so far is seems
that family history of specific treatment responses could
be predictive of response, whereas overall family history
of RA is not. The clinical usefulness of this information
is unknown, but it could mean that attention should
be paid to family history of responsiveness to different
treatment approaches.

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Conclusions antirheumatic therapies. Current evidence clearly sup‑

Family history of RA is an old concept, but fascinat‑
ing new data continue to emerge. Registry-based
total-population studies have validated findings from ear‑
lier studies in smaller and selected samples, and it is now
beyond doubt that family history is one of the strongest
risk factors for developing RA, conferring a twofold to
fourfold increase in risk among FDRs. Despite the pro‑
gress made in genetic association studies, this predictive
value is unlikely to be replaced by genetic markers any
time soon.
From an aetiological perspective, studies in FDRs
support heritability of about 40% for RA, which is lower
than the often-cited 60% that was based on twin studies.
Heritability is not modified by sex, but evidence suggests
that seropositive RA (for RF or ACPA) is more familial
than seronegative RA. However, there seems to be little
difference between seropositive and seronegative RA
in genetic and familial risk factors that are shared with
other arthritis-related diseases.
From a clinical point of view, information on fam‑
ily history might inform the work‑up for RA diagno‑
sis and predictions for disease course and response to
ports family history remaining an integral part of the
work‑up for RA, but indicates that care should also be
taken to ensure that relatives do indeed have RA, rather
than osteoarthritis or other arthralgia that confer no
increase in RA risk among FDRs. Asking about the
antirheumatic treatments that affected relatives receive
might be one way to discriminate between non‑RA
joint complaints and frank RA. Additionally, the risk
associated with family history decreases with increas‑
ing distance of relatives and, therefore, not searching
further than second-degree relatives seems reasonable.
Limited evidence so far suggests family aggregation of
treatment response but not disease course, but there are
no clear-cut findings. Yet, in situations where the choice
between two treatments is neutral in all other respects,
a family history of lack of response to one of them may
strengthen the choice for the other.
Finally, looking ahead, since the largest total-population
studies so far have used Scandinavian registers, repli‑
cations in other populations would be desirable. More
research is also needed on family history as a predictive
factor for prognosis.

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Author contributions
T.F. researched data for the article, J.A. and T.F. wrote the
article, and all authors made substantial contributions to dis-
cussions of the content and review/editing of the manuscript
before submission.
Competing interests statement
The authors declare no competing interests.

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