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Genome scan for quantity of hand osteoarthritisThe Framingham study.

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Vol. 46, No. 4, April 2002, pp 946–952
DOI 10.1002/art.10149
© 2002, American College of Rheumatology
Genome Scan for Quantity of Hand Osteoarthritis
The Framingham Study
S. Demissie,1 L. A. Cupples,1 R. Myers,2 P. Aliabadi,3 D. Levy,4 and D. T. Felson5
Objective. To search for markers linked to quantity of radiographic hand osteoarthritis (OA) in the
Framingham Heart Study.
Methods. The sample included 684 original cohort members and 793 offspring in 296 pedigrees.
Radiographic OA features evaluated included the
Kellgren/Lawrence (K/L) score, osteophytes, and joint
space narrowing (0–3 scale). Four quantitative phenotypes were computed from these measurements: sum of
K/L scores across hand joints, sum of osteophyte scores,
sum of joint space narrowing scores, and proportion of
affected joints. Prior to linkage analysis, these phenotypes were adjusted for age using a linear regression
analysis from which standardized residuals were computed. The regression analysis was performed separately for each sex and each generation. The variance
component model (SOLAR) was then applied to the
normalized scores of the residuals.
Results. The average age was 62 years for the
original cohort and 54 years for the offspring. Fifty
percent of the original cohort and 30% of their offspring
had at least 1 affected joint (K/L score >2). Heritability
ranged from 28% (proportion of joints affected with OA)
to 34% (sum of K/L scores). Eight chromosomal regions
indicated suggestive linkage (multipoint logarithm of
odds [LOD] score >1.5) for at least 1 phenotype; LOD
scores were highest for joint space narrowing, with a
multipoint LOD score ⴝ 2.96 on chromosome 1p at
D1S1665. Chromosomes 7, 9, 13, and 19 indicated consistent LOD score elevation for multiple OA phenotypes.
Conclusion. There are several chromosomes that
may harbor OA susceptibility genes. Further investigation of these regions using larger studies and finer maps
will be important to confirm linkage.
Osteoarthritis (OA) is the most common form of
arthritis and is among the leading causes of disability
throughout the world. As part of the complex etiology of
this disease, there is an increased recognition that a
genetic component plays an important role (1,2). Estimates of heritability of OA have ranged from 10% to
60% and may vary by the joint affected (2–4).
Although it is clear that risk of OA is affected by
inheritance, possible mutations or polymorphisms that
may increase the risk of disease are numerous. It is
conceivable that OA risk would be affected by abnormalities in such widely varying molecules as minor forms
of collagens, enzymes involved in synthesis or degradation of cartilage or other tissues in or around the joints,
hormone or growth factors or their receptors, and even
important structural molecules outside the cartilage that
give joints their shape. It is also possible that particular
structural abnormalities such as ligamentous laxity play a
role in increasing risk for disease (5). All of the possible
structural and functional susceptibilities make it hard to
make an educated guess about associations of particular
polymorphisms or mutations with OA. With a disease as
complex in etiology as OA, an approach to searching for
sites within the genome that accounts for variability in
individual risk of OA will provide insights to the most
likely genes or cluster of genes that affect disease risk. In
addition, recent studies (6) increasingly suggest that
susceptibility linkages may be joint specific.
Supported by NIH grant AR-20613 and by NIH/National
Heart, Lung, and Blood Institute contract N01-HC-38038.
S. Demissie, PhD, MPH, L. A. Cupples, PhD: Boston
University School of Public Health, Boston, Massachusetts; 2R. Myers,
PhD: Boston University School of Medicine, Boston, Massachusetts;
P. Aliabadi, MD: Brigham and Women’s Hospital, Boston, Massachusetts; 4D. Levy, MD: National Heart, Lung, and Blood Institute,
Framingham Heart Study, Framingham, Massachusetts; 5D. T. Felson,
MD, MPH: Clinical Epidemiology Research and Training Unit and
Arthritis Center, Boston University School of Medicine, Boston,
Address correspondence and reprint requests to David T.
Felson, MD, MPH, 715 Albany Street, A203, Boston University School
of Medicine, Boston, MA 02118. E-mail:
Submitted for publication July 13, 2001; accepted in revised
form November 2, 2001.
Linkage studies, those in which the genome is
explored to test whether sharing of particular anonymous markers correlates with sharing of an OA phenotype, have yielded varying results. Wright et al (7), in a
study of 66 sibpairs, reported that nodal hand OA was
linked to chromosome 2q. Finnish investigators also
reported a linkage of OA in the distal interphalangeal
(DIP) joints with chromosome 2q (8). Results of another
study of sibpairs with end-stage hip or knee OA, which
was defined as having undergone total hip or knee
replacement, also showed a linkage of hip disease with
chromosome 2q (9). While all suggested linkage with 2q,
the linkage sites on 2q differed substantially across
studies. These linkage studies were limited by small size
and by a focus on patients undergoing surgery for severe
disease. There have been no large-scale linkage studies
of OA from general populations. The recent focus on
hip OA has led to a neglect of disease at sites where the
disease is more prevalent, such as the hands and knees.
There also have been no linkage studies reported from
the US white population.
Here, we report the results of a whole genome
scan evaluating radiographic hand OA in the Framingham Heart Study (FHS) cohort and offspring, a
population-based group of multiple nuclear and extended families in which both parents (the cohort) and
their children (the offspring) were studied at adult ages.
Because most of our middle-aged and elderly subjects
had some evidence of radiographic OA, we focused our
inquiry into genetic linkage on the amount of disease,
summarizing the quantity of OA occurrence across hand
joints. While we were also interested in knee OA,
heritabilities of knee OA were not high enough to yield
reliable linkage information.
The FHS is a population-based, multigenerational
cohort study that began in 1948 and includes ⬎1,300 pedigrees
(10). The original cohort (parents in the families studied here)
was evaluated twice for the occurrence of hand OA (1967–70
and 1992–93). For the purposes of this study, the first radiograph of hands in a subject was used (11). As part of a study
investigating the heritability of OA (1993–94), we evaluated
the Framingham offspring who had at least 1 parent included
in the earlier OA studies, using the same techniques.
Hand OA was characterized radiographically using the
standard Kellgren/Lawrence (K/L) grading scheme (12). Radiographs were also read for osteophytes (OST) and for joint
space narrowing (JSN) using the Framingham OA atlas (13),
with each scored on a 0–3 scale. To ensure that radiographs in
offspring and cohort subjects would be read according to the
same standards, 1 musculoskeletal radiologist (PA) read all
hand radiographs, with films from offspring and cohort mixed.
For intraobserver agreement of ordinal-scale K/L scores, the
weighted kappa for all hand joints was 0.77; for the OST score,
it was 0.75; and for the JSN score, it was 0.74. All P values were
⬍0.001. When we defined joints as affected or not affected
based on a K/L score of ⱖ2, the kappa value was 0.82 and the
P value was ⬍0.001.
DNA was extracted from whole-blood or buffy coat
specimens using a standard protocol (14,15). DNA aliquots
from the largest 330 families were sent to the Mammalian
Genotyping Service Laboratory at the Marshfield Clinic
(Marshfield, WI), where a 10-cM genome scan was performed
(average heterozygosity 0.77). For quality control, 1) the
family relationships were verified on the basis of all available
markers by using the sib_kin program of the ASPEX package
(; and 2) Mendelian inconsistencies were identified and eliminated by using
the GENTEST program in PEDSYS (
public/software/pedsys/pedsys.html). Of these 330 families, a
genome-wide scan was carried out in the 296 extended pedigrees who had information on the OA traits derived from
⬃1,477 subjects with hand measurements.
Hand OA summary variables. Information from the
DIP joints, proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, and the carpometacarpal joint at the
base of each thumb was used, because these are the joints in
the hand most commonly affected by OA. There are 10 DIP
joints (we treated the IP joint of the thumb as a DIP), 8 PIP
joints, 10 MCP joints, and 2 thumb base joints; thus, a person
could have as many as 30 joints affected. Measurements on the
30 joints were obtained for K/L, OST, and JSN. The first hand
radiograph of cohort members was of the right hand only; thus,
OA scores for these readings were doubled, as previously
described (11). Based on these measurements, we defined 4
quantitative traits: the K/L-sum (sum of K/L scores), OST-sum
(sum of OST scores), JSN-sum (sum of JSN scores), and the
proportion of affected joints (K/L-proportion) (a joint was
considered affected when its K/L score was ⱖ2).
For the linkage analysis, each of the 4 measurements
was adjusted for age using a linear regression analysis from
which standardized residuals were computed. The regression
analysis was performed for men and women separately within
the original cohort and the offspring samples. Normalized
scores were then computed based on the ranks of standardized
residuals for the combined sample (i.e., the ranks of the
adjusted scores).
Statistical analysis. We used the computer program
SOLAR (16) for linkage analysis. All linkage analyses were
performed using the normalized deviates derived from the
standardized residuals. SOLAR uses a variance-components
approach that decomposes the total phenotypic variance into
quantitative trait locus (QTL; unobservable trait affecting a
major locus), residual polygenic, and residual nongenetic (or
random environmental) components. Linkage is assessed by
comparing the likelihood of a restricted model (a model where
the QTL variance is set to 0) with a full model in which the
variance due to the QTL is estimated. In the full model, the
QTL variance is estimated based on the correlation between
the proportion of genes shared that are identical by descent at
a single marker (for 2-point linkage analysis) or multiple
Table 1. Description of the subjects*
Table 2.
Heritability estimates
Study variable (no. in original cohort/
no. of offspring)
Hand measurement
⫾ SE
Sex, % men (684/793)
Age at time of hand radiograph,
years (684/793)
% of subjects with hand OA (680/792)†
Sum of K/L scores (0–120) (680/792)
% of joints with OA (680/792)
Sum of osteophyte scores (0–90)
Sum of joint space narrowing scores
(0–90) (681/792)
62.1 ⫾ 10.6
53.6 ⫾ 9.2
0.34 ⫾ 0.056
11.6 ⫾ 15.5
12.7 ⫾ 19
8.4 ⫾ 11.2
4.8 ⫾ 9.7
5 ⫾ 12
3.6 ⫾ 7.1
Sum of Kellgren/Lawrence
% of joints with
Sum of osteophyte scores
Sum of joint space
narrowing scores
0.28 ⫾ 0.057
0.33 ⫾ 0.055
0.30 ⫾ 0.054
4.2 ⫾ 8.1
1.4 ⫾ 4.4
* Significance of the mean heritability.
* Except where indicated otherwise, values are the mean ⫾ SD. OA ⫽
osteoarthritis; K/L ⫽ Kellgren/Lawrence.
† Those with at least 1 affected joint.
markers on a chromosome (for multipoint linkage analysis)
and the QTL.
To calculate multipoint linkage values, SOLAR uses
the Fulker and Cherny regression approach (17). Decisions
regarding linkage or no linkage are made using the logarithm
of odds (LOD) score, which is computed as the log10 of the
ratio of the likelihoods for the restricted and full models.
Linkage is considered to be significant genome-wide if the
LOD score exceeds 3.3, and to represent suggestive linkage if
it exceeds 1.5. The cutoff we used for suggestive linkage (LOD
score ⫽ 1.5, for a 10-cM genome map) is ⬃20% less than LOD
score ⫽ 1.9 (for a dense map) (18). In this article we have
reported results from both 2-point and multipoint linkage
analyses. Since multipoint linkage analysis is more powerful
and less prone to false-positive results, the results and conclusions regarding linkage are based on the multipoint LOD
scores only.
Table 1 presents statistics on the subjects included in the linkage analyses. The sample in this study
included 684 participants in the original cohort and 793
participants in the offspring study. The average age at
which the hand measurements were obtained was 62
years for the original cohort members and 54 years for
the offspring. The average unadjusted hand OA scores,
constituting a sum of the scores of all joints in the hands,
among the original cohort members were 11.6, 8.4, and
4.2 on the K/L, OST, and JSN scales, respectively. The
corresponding values for the offspring were 4.8, 3.6, and
1.4. Fifty percent of the original cohort members and
30% of their offspring had at least 1 affected joint. The
average proportion of joints with OA was 12.7% among
the cohort members and 5% among the offspring.
In Table 2, the estimated heritability values of the
various hand OA phenotypes are presented. These
estimates (⫾SE) ranged between 0.28 ⫾ 0.06 for the
proportion of joints affected with OA and 0.34 ⫾ 0.06
for the sum of K/L scores.
Linkage results are presented in Figures 1 and 2.
In the 2-point linkage analyses, there were 11 chromosomes (1–3, 7, 9, 11, 14, 16–19) with a maximum LOD
score ⬎1.5 for at least 1 of the 4 hand OA phenotypes
(Figure 1A). In the multipoint linkage, there were 8
chromosomes (1, 2, 7, 9, 11–13, 19) with maximum LOD
scores ⬎1.5 (Figure 1B) for at least 1 of the 4 hand
phenotypes. The LOD score was highest on chromosome 7 (LOD score ⫽ 2.86 for JSN-sum) in the 2-point
analysis and on chromosome 1 (LOD score ⫽ 2.96 for
JSN-sum) in the multipoint linkage analysis.
Figures 2a–h show the results of the multipoint
linkage analyses for chromosomes with a maximum
LOD score ⬎1.5. For chromosome 1, the peak LOD
score was obtained at 102 cM (D1S1665; LOD score ⫽
2.96 for JSN-sum); chromosome 2 at 48 cM (D2S405;
LOD score ⫽ 2.23 for JSN-sum); chromosome 7 at 50
cM (D7S817; LOD score ⫽ 2.32 for JSN-sum); chromosome 9 at 76 cM (D9S1122; LOD score ⫽ 2.29 for
JSN-sum); chromosome 11 at 77 cM (⬃D11S2371; LOD
score ⫽ 1.60 for JSN-sum); chromosome 12 at 166 cM
(D12S392; LOD score ⫽ 1.66 for JSN-sum); chromosome 13 at 36 cM (between D13S894 and D13S325;
LOD score ⫽ 1.61 for K/L-sum); and for chromosome
19 at 52 cM (D19S433; LOD score ⫽ 1.82 for JSN-sum)
and at 68 cM (D19S178; LOD score ⫽ 1.83 for K/Lsum).
Our linkage of hand OA, a heritable OA phenotype, in Framingham subjects suggests that there are
several chromosomes that may harbor OA susceptibility
genes. The ones that met the criteria for suggestive
linkage (multipoint LOD score ⬎1.5) include chromosomes 1, 2, 7, 9, 11–13, and 19. For those chromosomes
Figure 1. A, Maximum 2-point logarithm of odds (LOD) scores by chromosome for hand osteoarthritis (OA).
B, Maximum multipoint LOD scores by chromosome for hand OA. KL-Sum ⫽ sum of Kellgren/Lawrence scores;
KL-Prpn ⫽ proportion of affected joints; JSN ⫽ sum of joint space narrowing scores; OST ⫽ sum of osteophyte
with suggestive linkage, LOD scores were highest for the
JSN phenotype (Figures 2a–h).
The strengths of our study are considerable. First,
unlike other linkage studies that focus on subjects with
joint replacement or subjects with symptoms, we had
uniform, comprehensively obtained radiographs on all
Figure 2. Multipoint LOD scores by chromosome for hand OA. See Figure 1 for definitions.
subjects; all were read by 1 expert reader (PA) whose
readings have high reproducibility. Further, parents and
children were both studied at adult ages when OA was
sufficiently prevalent to be easily characterized. We were
able to evaluate several different related phenotypes,
and the data on linkage using these phenotypes provide
possibly valuable information suggesting different linkages with different elements of disease and help explore
the consistency of linkage across phenotype definitions.
To our knowledge, our study constitutes the first linkage
study of hand OA in the US white population.
Depending on the phenotype definitions, various
studies have suggested that ⬃10–60% of the variation in
OA is attributed to genetic factors (2–4). Our ageadjusted heritability estimates for the 4 hand OA phenotypes (ranging from 28% to 34%) were in the lower
range of those reported by others (2,4). Part of this
difference may be due to our inclusion of both men and
women, since we (3) and others (8) have reported higher
heritabilities in women. Also, our study includes both
middle-aged and elderly subjects, the latter group being
at highest risk of disease; our relatively low heritability
results may suggest that those with early disease who
have been the focus of other studies may have higher
disease heritability, a finding similar to that in studies of
other chronic diseases. This is one of the main reasons
we chose to study the first hand radiographs obtained
from our subjects rather than followup films obtained
more than 20 years later. Our heritability results may be
more generalizable to OA in the overall community than
are results of studies of much younger subjects.
A few linkage studies have indicated chromosomes 2q, 7p, and 11q as potential regions for markers
that are linked to OA susceptibility genes. Those indicating linkage to 2q showed suggestive linkage of severe
end-stage OA to 2q31 (D2S202 and D2S72 regions) (9),
suggestive linkage to DIP OA near the locus IL1R1 on
2q12-q14 (8), and a significant association between
nodal OA and 2q23-32 and 2q33-35 (7). In our study,
however, none of these regions on 2q showed linkage to
hand OA; the peak LOD score for chromosome 2 was
observed on 2p at 48 cM (D2S405). Otherwise, our
results indicated suggestive linkage to regions on 7p
(⬃D7S817), ⬃10–30 cM proximal to 7p15-p21, the
regions indicated in the Finnish study (8); and to 11q
(D11S2371), ⬃10–20 cM proximal to markers D11S901,
D11S1358, and D11S35, reported by Chapman et al
Other regions that indicated suggestive linkage,
with multipoint LOD scores ⬎1.5, were on chromosomes 1, 9, 12, 13, and 19. In fact, the highest LOD score
in the genome-wide scan was obtained on 1p (LOD ⫽
2.96, ⬃D1S1665 region). Although the LOD scores in
our study were generally highest for the JSN phenotype,
on chromosomes 7, 9, 13, and 19 there were consistent
LOD score elevations for multiple hand phenotypes
(Figures 2c, d, g, and h). In addition, chromosomes 7 and
19 each showed suggestive linkage evidence with multipoint LOD scores ⬎1.5 for ⬎1 phenotype (chromosome
7 for JSN-sum and K/L-proportion and chromosome 19
for JSN-sum and K/L-proportion).
The high LOD scores for JSN may indicate that
the chromosomal sites represent genes influencing cartilage loss rather than genes whose products are involved
with bony response to disease, which might be reflected
if LOD scores were highest for osteophytes. While this
does not necessarily indicate that JSN should be the
phenotype of interest for genetic studies, it suggests that
the JSN phenotype may be separable in some circumstances from the phenotype for other radiographic features. It is important to note that the heritability estimates from this study suggest a strong genetic
involvement for all 4 OA phenotypes.
A number of candidate genes lie within the
regions that showed suggestive linkage to OA. For
example, the region of high LOD score on 2p is near the
gene for tissue inhibitor of metalloproteinases 3, a
matrix inhibitor of active stromelysin. On chromosome
19, our marker is close to the transforming growth factor
␤1 gene, and, on chromosome 11, it lies close to the ␣
estrogen receptor gene.
It is not surprising that we did not see overlapping results (regions) among the aforementioned studies
since they vary in sample sizes, analysis strategies, and,
perhaps most important, in OA phenotype definitions.
Moreover, the results from various studies, including
ours, constitute only suggestive evidence of linkage
(possibly due to insufficient statistical power). Only
Chapman et al (19) found significant linkage (LOD
score ⫽ 3.15) between D11S1358 and D11S35. Therefore, it will be important to undertake further investigation of several chromosomal regions using finer maps
and larger studies to confirm linkage. The higher LOD
scores on 1p and 2p (our study), the suggestive linkage
evidence for 7p, 11q, and 2q (other studies), and the
consistent signal of linkage to several hand OA phenotypes for regions on chromosomes 9, 13, and 19 (our
study), in particular, warrant further investigation.
The study has a number of potential limitations.
First, while we were also interested in evaluating linkage
to knee OA, the low heritabilities for this trait prevented
further analyses. A simulation analysis of power in our
sample for knee data indicated that we had 80% power
to detect a locus when it accounts for 25% heritability or
more. Our heritability estimates for knee OA were
generally lower than this estimate. Second, no hip OA
data were available in this population. Third, although
there was very high intraobserver reliability in the
assessment of OA, the presence of measurement errors
or misclassification in the phenotype definitions could
not be ruled out. For example, the use of only the right
hand OA data for the cohort members could have
resulted in phenotype misclassification and might have
underestimated the presence of linkage. Finally, it is
possible that the linkage findings in this study represent
false-positive signals. It is also possible that true linkages
were not detected because of insufficient power. While
our sample size is typical of many family studies, it is
clear that only QTLs with large effects can be detected
through linkage analyses. Our study only has power of
ⱖ80% to detect a QTL that accounts for ⬎25% of the
total variation in the trait, a threshold that may not be
reached for a complex trait such as OA.
In summary, we report the results of a genome
scan suggesting linkage of multiple chromosomal sites
that may harbor genes for hand OA. While we cannot
confirm previous reports of linkage to chromosome 2q,
we can corroborate sites of potential interest on 7p and
11q and report additional promising sites on several
other chromosomes.
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