Download Autosomal Genome Scan for Loci Linked to Blood

Autosomal Genome Scan for Loci Linked to Blood Pressure
Levels and Trends Since Childhood
The Bogalusa Heart Study
Wei Chen, Shengxu Li, Sathanur R Srinivasan, Eric Boerwinkle, Gerald S. Berenson
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Abstract—Genetic loci influencing the long-term levels and trends of blood pressure over time were investigated using 775
white siblings, ages 13 to 43 years, enrolled in the Bogalusa Heart Study, and 357 microsatellite markers on the 22
autosomal chromosomes. Subjects had been examined serially 2 to 12 times with 4365 serial observations over an
average of 22 years from childhood to adulthood. Total and incremental area under the curve was calculated based on
a cubic growth curve and used as long-term levels and trends, respectively. After adjusting for age, sex, and body mass
index, heritability estimates of total area were 0.66 for systolic and 0.68 for diastolic blood pressure. Heritability of
incremental area was 0.38 for systolic and 0.46 for diastolic blood pressure. Significant linkage to the total area of
diastolic blood pressure (peak logarithm of odds [LOD]⫽3.9 at 73 cM) was observed on chromosome 2, with a region
spanning from 44 cM to 103 cM showing supporting linkage evidence of LOD ⬎3.0. In addition, suggestive linkage
for total area of systolic (LOD⫽1.6 at 182 cM) and diastolic blood pressure (LOD⫽2.0 at 36 cM) on chromosome 4
and diastolic blood pressure incremental area (LOD⫽2.2 at 28 cM) on chromosome 18 was noted. Several hypertension
candidate genes such as ␣-adducin, ␤-adducin, sodium bicarbonate co-transporter, and G protein-coupled receptor
kinase 4 are located in these regions. Linkage evidence found in this community-based study indicates that regions on
these chromosomes harbor genetic loci that affect the propensity for development of hypertension from childhood.
(Hypertension. 2005;45:954-959.)
Key Words: blood pressure
E
time within the same individual.8,9 This notion is supported
by earlier findings from studies on genetics and epidemiology
of blood pressure.10,11 Therefore, measures of long-term
levels and trend of blood pressure may provide better insight
into the identification of susceptibility loci for blood pressure
or hypertension.
The Framingham Offspring Study has reported genomewide linkage results of blood pressure in terms of long-term
levels and trend using serial measurements during adulthood.10,12,13 However, information on the genetic loci linking
longitudinal changes in blood pressure from childhood to
adulthood is still limited. Longitudinal observations from the
Bogalusa Heart Study, a community-based epidemiologic
study of early natural history of cardiovascular risk factors
beginning in childhood,14 provide an opportunity to examine
the susceptibility loci influencing both between-person and
within-person variability in blood pressure from childhood to
young adulthood. This report provides genome-wide linkage
analysis in white siblings using measures of long-term levels
and trend derived from serial measurements of blood pressure
extending over an average of 22 years beginning in childhood.
ssential hypertension is a polygenic disorder that results
from the interplay of multiple susceptibility genes and
environmental factors.1 Numerous genome-wide linkage
studies to localize genes influencing blood pressure and
hypertension status in a number of populations and ethnic
groups have found linkage evidence in regions on multiple
chromosomes.2 However, most linkage studies on blood
pressure and hypertension have thus far been cross-sectional
in nature, representing between-person variability at a specific time point only.
Blood pressure increases with age at different rates.3,4 In
addition to levels, genes may also affect the longitudinal
trends of blood pressure that represent within-person variability. A substantial genetic contribution to the changes in blood
pressure over time has been demonstrated in longitudinal
twin and family studies.5,6 A concept of “variability genes,”
whose expression depends on environmental exposure, is
proposed to explain the within-person variability.7 Further,
using serial measurements of a trait at multiple time points
dilutes the measurement errors and minimizes the short-term
influences when the trait is subject to variation from time to
Received February 3, 2005; first decision February 3, 2005; revision accepted February 28, 2005.
From the Tulane Center for Cardiovascular Health and Department of Epidemiology (W.C., S.L., S.R.S., G.S.B.), Tulane School of Public Health &
Tropical Medicine, New Orleans, La; and the Human Genetics Center and Institute of Molecular Medicine (E.B.), University of Texas–Houston Health
Science Center, Houston, Tex.
Correspondence to Gerald S. Berenson, MD, Tulane Center for Cardiovascular Health, 1440 Canal St, Suite 1829, New Orleans, LA 70112. E-mail
[email protected]
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000161881.02361.11
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Chen et al
Genetic Loci for Blood Pressure Since Childhood
955
Figure 1. The area under the curve
(AUC) of systolic blood pressure (SBP)
derived from a growth curve model in
white males. Individual 1: examined at
ages of 10, 15, 19, 23, 29, and 35. Individual 2: examined at ages of 11, 16, 20,
26, 30, and 38.
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Materials and Methods
Study Cohort
In the community of Bogalusa, Louisiana, 7 cross-sectional surveys
of children aged 3 to 17 years were conducted between 1973 and
1994. In addition, 8 cross-sectional surveys of young adults aged 18
to 43 years who had been previously examined as children were
conducted between 1976 and 2003. This panel design of repeated
cross-sectional examinations conducted approximately every 3 years
resulted in serial observations on the cohort. Eligible study subjects
for this analysis comprise white siblings who participated 2 to 12
times (at least once in childhood and once in adulthood) during the
period of 1973 to 2003 from childhood to adulthood. Siblings were
identified based on Bogalusa sibship census database. After validation of the reported sibling relationship, there were 775 white
siblings, ages 13.0 to 43.2 years at last examination, from 339
families (representing 517 full sib-pairs and 38 half sib-pairs) with
4365 observations. A majority of siblings (91.4%) were screened 3
or more times, and the average number of times examined was 5.6.
The follow-up period ranged from 5 to 29 years (average, 22 years).
This study was approved by the Institutional Review Board of the
Tulane University Health Sciences Center. All adult subjects gave
informed consent at each examination. For subjects younger than age
18 years, consent from parents was obtained.
Examinations
All examinations followed the same basic protocols described
elsewhere.15 Indirect blood pressures were recorded in a relaxed
atmosphere with Hg sphygmomanometers. Subjects were randomly
assigned to 2 different stations. Well-trained observers recorded
systolic blood pressure (SBP) at first and diastolic blood pressure
(DBP) at fourth and fifth Korotkoff phases on the right arm in a
relaxed, sitting position. Each observer recorded 3 measurements,
resulting in a total of 6 readings, and the average was used as a blood
pressure value at a single time point. The fourth phase was used for
longitudinal analyses of DBP in children and adults because our
earlier study showed the fourth phase to be more reliably measured
in childhood and more predictive of adult hypertension.16 Blood
pressure values were set to missing for subjects (n⫽51) who used
antihypertensive medications at any examinations, and the remaining
measurements were used for linkage analysis.
Genotyping
Genotyping of 357 highly polymorphic microsatellite markers on 22
autosomal chromosomes was accomplished using fluorescently labeled primers and an Applied Biosystems 377 sequencer (Foster
City, Calif). The marker locations were determined using the genetic
map provided by the Marshfield Medical Research Foundation. The
mean spacing between adjacent markers was 9.0 cM (range, 0 to 25.5
cM). The average heterozygosity of the 357 markers was 0.77, with
a range of 0.56 to 0.92. Details of the marker names and locations are
available by request. The reproducibility of the genotyping for each
marker was evaluated in 81 pairs of blind duplicate DNA samples.
There was, on average, 99.7% concordance between the blind
duplicate pairs, and no marker had an agreement rate ⬍96%.
Statistical Analysis
A cubic growth curve of blood pressure from childhood to adulthood
was constructed for males and females separately using a random
effects model with Statistical Analysis Software (SAS) Proc
MIXED. In addition to the fixed population effects, the mixed model
also incorporates random effects and has the form:17
Y⫽共␤0⫹b0兲⫹共␤1⫹b1)age⫹共␤2⫹b2兲age2⫹共␤3⫹b3兲age3⫹e
where ␤⫽(␤0, ␤1, ␤2, ␤3)⬘ is a vector of fixed effect parameters, and
b⫽(b0, b1, b2, b3)⬘ is a vector of random effect parameters. This
random effects model allows the intercept, linear, and nonlinear
parameters to vary from individual to individual, and the random
coefficients represent the difference between the fixed population
parameters and the true values for the individual. It also allows for
repeated measurements and different numbers of unequally spaced
observations across individuals.17 The fixed effect parameter estimates of the cubic growth curves of blood pressure in the sibling
cohort were:
Male: SBP⫽112.6⫹0.86age⫺0.56age2⫹0.03age3;
DBP⫽68.2
⫹0.92age⫺0.22age ⫹0.006age
2
3
Female: SBP⫽108.5⫹0.34age⫺0.75age2⫹0.06age3;
DBP⫽68.9
⫹0.53age⫺0.47age ⫹0.03age
2
3
Age was centered by subtracting 17.2, the term age2 was divided by
10, and age3 was divided by 20 to improve model fitting. Regression
coefficients were all significant (P⬍0.0001) except for 0.006
(P⫽0.097) for DBP in males. As shown in Figure 1, using SBP in
males as an example, the area under the curve (AUC) was calculated
as the integral of the predicted growth curve parameters during the
follow-up period for each individual.11,18 Total AUC is a measure of
long-term levels, and incremental AUC (total AUC ⫺ baseline
AUC) measures combined linear and nonlinear long-term trends.
Because different individuals had different follow-up periods in this
study cohort, the AUC values were divided by the number of
follow-up years. The AUC method has advantages over the average
value in that it can measure both long-term level and trend. Further,
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Hypertension
TABLE 1.
May 2005
Means (SD) of Age, BMI, and BP of White Siblings
Variable
Male
(n⫽359)
Female
(n⫽416)
Total
H2
(n⫽775)
TABLE 2. Peak Multipoint LOD Scores (Positions, cM) for BP
in White Siblings
Systolic BP
Age at first examination
9.3 (3.1)
9.1 (3.1)
9.2 (3.1)
—
Age at last examination
31.0 (7.1)
31.1 (6.9)
31.1 (7.0)
—
Chromosome
BMI at first examination
17.4 (3.2)
17.4 (3.5)
17.4 (3.4)
—
BMI at last examination
28.0 (5.9)
27.8 (7.8)
27.9 (6.9)
—
Total AUC
Diastolic BP
Total
AUC
Incremental
AUC
Total
AUC
Incremental
AUC
1
0.50 (6)
0.80 (114)
1.05 (198)
0.64 (86)
2
0.60 (87)
0.29 (259)
3.94 (73)
0.42 (170)
3
0.42 (90)
0.20 (129)
0.43 (161)
0.39 (0)
Systolic BP
109.9 (7.5)
106.5 (5.8)*
108.1 (6.8)
0.66
4
1.63 (182)
0.99 (39)
2.04 (36)
0.55 (14)
Diastolic BP
69.5 (5.5)
68.5 (4.1)*
69.0 (4.8)
0.68
5
0.15 (65)
1.06 (146)
0.60 (36)
0.22 (14)
6
0.30 (157)
1.23 (146)
0.64 (20)
0.93 (152)
Incremental AUC
Systolic BP
10.9 (4.5)
8.1 (5.2)*
9.4 (5.1)
0.38
7
0.23 (128)
0.21 (136)
0.70 (140)
0.43 (141)
Diastolic BP
10.1 (3.3)
8.4 (3.5)*
9.2 (3.5)
0.46
8
0.39 (0)
0.47 (62)
1.38 (155)
0.50 (154)
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AUC indicates area under the curve (mm Hg) divided by the number of
follow-up years; BMI, body mass index (kg/m2); BP, blood pressure; H2,
heritability.
*P⬍0.001 for sex difference.
the long-term trend (linear and nonlinear) estimated using multiple
measurements is more reliable than using 2–time-point data.
The biological relationship among siblings was verified using the
RELTEST program (S.A.G.E. version 4.3)19 based on 357 autosomal
markers. After verification of full-sibling and half-sibling relationships, genotype inconsistencies because of non-Mendelian inheritance were identified for each marker using the MARKERINFO
program of S.A.G.E. Those genotypes of single individuals proven to
be inconsistent were set to missing for that marker only. Maximum
likelihood estimation of the marker allele frequencies was performed
using the FREQ program of S.A.G.E. in siblings.
A variance component method was implemented to test for
evidence of linkage of a quantitative trait locus for total and
incremental AUC of blood pressure. The genetic variance attributable to a specific chromosomal location was estimated based on
specifying the expected genetic covariance between relatives as a
function of the identity-by-descent relationships at a quantitative trait
locus.20 Parameter estimates were calculated at 1-cM intervals along
each chromosome. Heritability analysis and 2-point and multipoint
variance component linkage analyses were performed using SOLAR
2.0,21 incorporating a simultaneous correction of covariates affecting
the longitudinal levels and changes in blood pressure. These covariates were age (an average of ages at multiple time points), sex, and
body mass index for total AUC. In addition, baseline blood pressure
values were also included in the model for incremental AUC to
control the regression-to-the-mean influence.
Results
As shown in Table 1, mean values of total and incremental
AUC for SBP and DBP in males were significantly greater
than those in females (P⬍0.001). Baseline blood pressure
was negatively and significantly correlated with incremental
AUC (r⫽⫺0.22 for SBP; r⫽⫺0.30 for DBP), adjusting for
sex, baseline age, and baseline body mass index. In the
polygenic model of variance components analyses by SOLAR, adjusting for age, sex, and body mass index, heritability
estimates of total AUC were 0.66 for SBP and 0.68 for DBP.
In contrast, heritability estimated using a single measurement
at first examination was 0.49 for SBP and 0.36 for DBP.
These values at the last examination were 0.45 for SBP and
0.46 for DBP. Heritability of incremental AUC was 0.38 for
SBP and 0.46 for DBP, adjusting for baseline blood pressure
in addition to the aforementioned covariates. The age range
was 4 to 18 years at first examination, and 13 to 43 years at
9
0.05 (17)
0.69 (64)
0.73 (141)
0.65 (131)
10
0.40 (99)
0.91 (0)
0.26 (14)
0.24 (5)
11
0.18 (129)
0.19 (142)
0.06 (2)
0.23 (52)
12
0.49 (124)
0.30 (9)
1.54 (71)
0.46 (10)
13
0
0.98 (9)
0.62 (111)
0.91 (36)
14
0.04 (23)
0.76 (118)
1.53 (15)
0.60 (0)
15
0.93 (123)
0.31 (36)
0.66 (123)
0.29 (36)
16
0.53 (39)
0.66 (20)
0.22 (51)
1.47 (17)
17
0.86 (40)
0.07 (1)
1.18 (94)
0.01 (33)
18
0
0.97 (37)
0.32 (81)
2.17 (28)
19
0.37 (16)
0.68 (25)
0.37 (16)
0.48 (101)
20
0.42 (18)
0.69 (89)
0.59 (3)
0.02 (99)
21
0.34 (45)
0.25 (3)
22
0.11 (38)
0
0
0.21 (13)
0
0
last examination. Twenty-one subjects did not have adulthood
blood pressure values because they were using antihypertensive medications and their blood pressure values were set to
missing.
Table 2 gives the maximum multipoint logarithm of odds
(LOD) scores and locations for blood pressure AUC on 22
chromosomes. Total AUC of DBP showed significant linkage
(LOD⫽3.9 at 73 cM) on chromosome 2. The point-wise
empirical probability value corresponding to the LOD score
of 3.9 is 0.00001. Taking into account multiple tests at every
1 cM in the present study, the genome-wide significance level
is ⬍0.02 for the LOD score of 3.9 based on the genome-wide
simulation study of sib-pairs.22 In addition, suggestive linkage was found for total AUC of DBP (LOD⫽2.0 at 36 cM) on
chromosome 4 and incremental AUC of DBP (LOD⫽2.2 at
28 cM). For detailed LOD scores on each chromosome,
please see http://hyper.ahajournals.org.
Figure 2 shows multipoint LOD scores and locations on
chromosome 2. A LOD score peak (LOD⫽3.9) for DBP total
AUC was located at 73 cM from the p-terminal, with a region
spanning from 44 cM to 103 cM supported by linkage
evidence of LOD ⬎3.0. Markers within this region showing
positive 2-point linkage were D2S305 (LOD⫽2.1), D2S337
(LOD⫽2.5), D2S388 (LOD⫽2.3), D2S391 (LOD⫽2.1),
D2S2110 (LOD⫽2.6), and D2S2163 (LOD⫽2.4). There was
no linkage evidence for DBP incremental AUC and SBP on
chromosome 2. As shown in Figure 3, a LOD score peak
Chen et al
Genetic Loci for Blood Pressure Since Childhood
957
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Figure 2. Multipoint linkage results for total and incremental
AUC for blood pressure in white siblings on chromosome 2: The
Bogalusa Heart Study. AUC indicates area under the curve
(mm Hg) divided by the number of follow-up years. Total AUC
was adjusted for age, sex, and body mass index; incremental
AUC was adjusted for age, sex, body mass index, and baseline
blood pressure.
Figure 4. Multipoint linkage results for total and incremental
AUC for blood pressure in white siblings on chromosome 18:
The Bogalusa Heart Study. AUC⫽area under the curve (mm Hg)
divided by the number of follow-up years. Total AUC was
adjusted for age, sex, and body mass index; incremental AUC
was adjusted for age, sex, body mass index, and baseline blood
pressure.
(LOD⫽2.0) for DBP total AUC was observed at 36 cM on
chromosome 4 near the marker D4S2994 (2-point
LOD⫽2.1). The same location showed weak linkage to SBP
total AUC (LOD⫽1.1 at 35 cM) and SBP incremental AUC
(LOD⫽0.99 at 39 cM). Also, SBP had LOD score peaks near
the q-terminal on chromosome 4 (LOD⫽1.6 at 182 cM for
total AUC and LOD⫽0.95 at 170 cM for incremental AUC).
In Figure 4, DBP incremental AUC showed a LOD score
peak (LOD⫽2.2 at 28 cM) on chromosome 18 near the
marker D18S843 (2-point LOD⫽2.0). SBP incremental AUC
showed a maximum LOD score of 0.97 at 37 cM. No linkage
evidence was found for total AUC on chromosome 18.
Figure 3. Multipoint linkage results for total and incremental
AUC for blood pressure in white siblings on chromosome 4: The
Bogalusa Heart Study. AUC⫽area under the curve (mm Hg)
divided by the number of follow-up years. Total AUC was
adjusted for age, sex, and body mass index; incremental AUC
was adjusted for age, sex, body mass index, and baseline blood
pressure.
Discussion
In the present study, serial measurements of blood pressure
from childhood to young adulthood were used for genomewide linkage analysis. Children and relatively younger adults
of this cohort rather than older age groups may be more suited
to investigate hypertension susceptibility loci because the
genetically predisposed individuals tend to express blood
pressure changes earlier in childhood despite the smaller
variations. Further, blood pressure levels in younger subjects
are relatively unobscured by prolonged lifestyle habits, less
cumulative environmental exposure, and medical treatments.
Blood pressure measurements in untreated subjects were used
as a quantitative trait in this study, in contrast to qualitative
phenotype of hypertension status used in other studies.
The number of genome scans for hypertension or blood
pressure has been increasing over the past decade.2 Most
studies reported weak or suggestive linkage; a few studies
attained significant linkage evidence.10,23–27 The present study
found significant linkage evidence (LOD⫽3.9) at 73 cM on
chromosome 2p13 for the long-term levels of DBP from
childhood to young adulthood measured by total AUC.
Although a number of regions on multiple chromosomes have
been previously found in ⬎1 study,2 the region between 40
and 140 cM from the tip of the p-arm of chromosome 2
showed the most consistent and overwhelming linkage evidence for blood pressure loci.25–34 The finding on chromosomes 2 from this study replicates at least 10 other studies.25–34 The Family Blood Pressure Program selected the
region between 40 and 140 cM on chromosome 2 on the basis
of convincing linkage evidence in the previous studies to
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May 2005
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identify underlying candidate susceptibility genes for hypertension using combined positional candidate gene methods.
Sodium bicarbonate co-transporter (SLC4A5) gene was identified as a primary candidate gene for hypertension in this
region, with a LOD score of 2.84 at 93 cM.28 In the present
study, the region spanning from 44 cM to 103 cM showed
supporting linkage evidence of LOD ⬎3.0 (Figure 1). There
are 6 markers (D2S305, D2S337, D2S388, D2S391,
D2S2110, and D2S2163) within or near this region that had
2-point LOD scores of 2.11 to 2.57; D2S2110 located at 91
cM had the highest LOD score of 2.57. Of great interest,
␤-adducin gene is located in this region, which has been
previously implicated in blood pressure variation in animals
and humans.35 Further, a 3-stage genome-wide search in a
12-generation pedigree demonstrated the most striking linkage result on chromosome 2p25-p24 region (9 to 23 cM),
designated essential hypertension susceptibility 3 gene.26 The
finding was strengthened by the evidence for linkage with
marker D2S168 in a genome-wide scan of affected
sib-pairs.34
In the previous longitudinal studies, significant genetic
heritabilities5 and a recessive major gene effect6 have been
demonstrated for the changes in blood pressure over time. In
the Framingham Offspring Study, blood pressure slope and
curvature over time during adulthood have been found to link
to regions on chromosomes 7, 18, and 20.12,13 In this study,
we found a LOD peak at 28 cM from the p-terminal on
chromosome 18 for the incremental AUC of diastolic blood
pressure, a combination of linear slope and nonlinear curvature. Positive linkage has also been observed around this
region for long-term blood pressure levels10 and essential
hypertension36 in other studies. Genes in 18p11 region are
glucocorticoid deficiency-1 and melanocortin-2 receptor, a
member of the G protein-coupled receptor family, which are
involved in the regulation of cortisol secretion. The findings
from the present and previous studies provide supporting
evidence for the concept of “variability genes,” which may
influence within-person variability in phenotypes over time
through the gene– environment interactions.7
There is evidence for the role of ␣-adducin gene in blood
pressure regulation and hypertension in animal studies and
some human populations.35 Suggestive linkage to DBP total
AUC was noted in this study on chromosome 4p16 where the
␣-adducin gene is located. Significant linkage evidence for
blood pressure was also reported in this region in Dutch
dyslipidemic families. However, no evidence was observed
for an association between ␣-adducin polymorphisms and
blood pressure in the same sample.24 In addition, another
hypertension candidate gene, G protein-coupled receptor
kinase 4,37 is closely linked to ␣-adducin gene in this
location.
Perspectives
Essential hypertension is a polygenic disorder that results
from the interplay of multiple susceptibility genes and environmental factors. However, most linkage studies on blood
pressure and hypertension have thus far been cross-sectional
in nature. Most previous studies reported weak or suggestive
linkage; a few studies attained significant linkage evidence.
Using serial measurements of blood pressure at multiple time
points dilutes the measurement errors and minimizes the
short-term influences. Therefore, measures of both long-term
levels and trend of blood pressure may provide better insight
into the identification of susceptibility loci for blood pressure
or hypertension. Further, a substantial genetic contribution to
the changes in blood pressure over time has been demonstrated. There is a need to investigate genetic loci for both
levels and rate of change of blood pressure over time. The
significant and suggestive linkage with long-term levels and
trends of blood pressure found in this community-based study
indicates that regions on these chromosomes harbor genetic
loci that affect the propensity for development of hypertension from childhood. The quantitative trait loci identified in
this study along with earlier studies serve as a basis for further
fine-mapping strategies to identify and test responsible genes
involved in the cause of hypertension.
Acknowledgments
This study was supported by grants HL-38844 from the National
Heart, Lung, and Blood Institute and AG-16592 from the National
Institute on Aging. Some of the results of this paper were obtained by
using the program package S.A.G.E., which is supported by a US
Public Health Service Research Resource Grant (1 P41 RR03655)
from the National Center for Research Resources.
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Hypertension. 2005;45:954-959; originally published online April 4, 2005;
doi: 10.1161/01.HYP.0000161881.02361.11
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Appendix Figure Legend
Multipoint linkage results for total and incremental AUC for blood pressure in
white siblings on chromosomes 1 to 22: The Bogalusa Heart Study
AUC=area under the curve (mmHg) divided by the number of follow-up years.
Total AUC was adjusted for age, sex and BMI; incremental AUC for age, sex, BMI
and baseline blood pressure.
4
Total AUC
SBP
Incremental AUC
3
Chromosome 1
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
150
Location (cM)
Figure I
200
250
300
4
Total AUC
Incremental AUC
SBP
3
Chromosome 2
2
LOD Score
1
0
4
DBP
3
2
1
0
0
Figure II
100
Location (cM)
200
300
4
Total AUC
SBP
Incremental AUC
3
Chromosome 3
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
150
Location (cM)
Figure III
200
250
4
Total AUC
SBP
Incremental AUC
3
Chromosome 4
2
LOD Score
1
0
4
DBP
3
2
1
0
0
Figure IV
50
100
Location (cM)
150
200
4
Total AUC
Incremental AUC
SBP
3
Chromosome 5
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure V
150
200
4
Total AUC
Incremental AUC
SBP
3
Chromosome 6
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure VI
150
200
4
Total AUC
Incremental AUC
SBP
3
Chromosome 7
2
LOD Score
1
0
4
DBP
3
2
1
0
0
Figure VII
50
100
Location (cM)
150
200
4
Total AUC
Incremental AUC
SBP
3
Chromosome 8
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure VIII
150
200
4
Total AUC
Incremental AUC
SBP
3
Chromosome 9
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure IX
150
200
4
Total AUC
Incremental AUC
SBP
3
Chromosome 10
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure X
150
200
4
Total AUC
Incremental AUC
SBP
3
Chromosome 11
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure XI
150
4
Total AUC
Incremental AUC
SBP
3
Chromosome 12
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure XII
150
200
4
Total AUC
Incremental AUC
SBP
3
Chromosome 13
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure XIII
150
4
Total AUC
Incremental AUC
SBP
3
Chromosome 14
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure XIV
150
4
Total AUC
Incremental AUC
SBP
3
Chromosome 15
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure XV
150
4
Total AUC
Incremental AUC
SBP
3
Chromosome 16
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure XVI
150
4
Total AUC
Incremental AUC
SBP
3
Chromosome 17
2
LOD Score
1
0
4
DBP
3
2
1
0
0
50
100
Location (cM)
Figure XVII
150
4
Total AUC
SBP
Incremental AUC
3
Chromosome 18
2
LOD Score
1
0
4
DBP
3
2
1
0
0
Figure XVIII
50
100
Location (cM)
150
4
Total AUC
SBP
Incremental AUC
3
Chromosome 19
2
LOD Score
1
0
4
DBP
3
2
1
0
0
Figure XIX
50
100
Location (cM)
150
4
Total AUC
SBP
Incremental AUC
3
Chromosome 20
2
LOD Score
1
0
4
DBP
3
2
1
0
0
Figure XX
25
50
Location (cM)
75
100
4
Total AUC
SBP
Incremental AUC
3
Chromosome 21
2
LOD Score
1
0
4
DBP
3
2
1
0
0
Figure XXI
10
20
30
Location (cM)
40
50
4
Total AUC
SBP
Incremental AUC
3
Chromosome 22
2
LOD Score
1
0
4
DBP
3
2
1
0
0
Figure XXII
10
20
30
Location (cM)
40
50