Participants were from Cohort 1 and Cohort 2 of the Framingham Heart Study data set provided by the Genetic Analysis Workshop 13 (GAW13). In Cohort 1, 1231 individuals (583 males and 630 females) with a mean baseline age of 41.5 years (ranging from 29.0 to 62.0) were included. Cohort 2 included 1672 individuals (826 males and 846 females) with a mean baseline age of 32.7 years (ranging from 5.0 to 64.0). Some participants in the two cohorts were from the same pedigree, and in total 330 pedigrees were identified. Among these pedigrees, 1702 individuals were further genotyped for genomic scanning.
In this study, we considered five measures that are included in the operational criteria for the metabolic syndrome as defined by the Adult Treatment Panel III (ATP III) . Because the data on waist circumference, which measures abdominal obesity, were not provided in the Framingham Heart Study data set, we instead employed overall obesity as measured by a BMI > 30 kg/m2. The cut-off points of hypertension in the Framingham Heart Study data set were slightly more stringent than those recommended in the ATP III criteria (≥ 130 / ≥ 85 mm Hg). The specific criteria adopted in this study were as follows: 1) Blood pressure: systolic blood pressure (SBP) ≥ 140 mm Hg or diastolic blood pressure (DBP) ≥ 90 mm Hg, or under anti-hypertension treatment; 2) Obesity: BMI > 30 kg/m2; 3) Fasting glucose: ≥ 110 mg/dl; 4) Triglycerides: ≥ 150 mg/dl; and 5) HDL cholesterol: < 40 mg/dl (men) or < 50 mg/dl (women). The diagnosis of the metabolic syndrome was made when three or more of the criteria were met. Phenotypic data provided in the GAW13 included those for the first 40 years of follow-up in the Cohort 1 (Exams 1 through 21) and those of the first 20 years of follow-up in the Cohort 2 (Exams 1 through 5).
Sibling recurrence risk ratio (λ
) is defined as sibling recurrence risk (K
) divided by the population prevalence (K
). Since the original pedigrees were not ascertained via any particular phenotype considered in the present study, the determination of proband status is problematic. Under this circumstance, we considered every diseased individual as a proband and employed the method for estimating sibling recurrence risk (K
) when proband status is unknown as proposed by Olson and Cordell :
where ns(a)is the number of sibships of size s with a affecteds. This estimator of K
has been shown to be unbiased and consistent when the ascertainment is complete , which is the case for this study. The denominator of λ
, the population prevalence, was estimated from the whole cohort. Since the age range of Cohort 2 was wide, we limited the analysis of Cohort 2 to those aged between 30 and 60 years old.
We estimated cross-sectional λ
for each exam and then calculated the standard deviation and the range of the estimated λ
across the exams. Furthermore, we defined a lifetime λs,e≥tas the condition that an individual had ever had the episode fulfilling the criterion at least t times during the whole study period. As t increases, the person is supposed to have higher probability of carry the genetic susceptibility of the phenotype. In assessing the lifetime λ
for the metabolic syndrome, any particular criterion was considered fulfilled if the individual had ever any measures above the threshold during lifetime, and a positive diagnosis was given if three or more criteria were met in this way.
For each component and the metabolic syndrome per se, we then performed nonparametric linkage analyses for the pedigrees using GENEHUNTER  with the option of all affected pairs in a pedigree. Four kinds of phenotype definition were employed: cross-sectional diagnosis, lifetime diagnosis with episode ≥ 1, lifetime diagnosis with episode ≥ 2, and lifetime diagnosis with episode ≥ 3. For the cross-sectional diagnosis, we chose the data from Exam 11 for Cohort 1 members and Exam 1 for Cohort 2 members because the two test points were chronologically close to each other. However, for Cohort 1 members, the height was from Exam 10 and the glucose level was from Exam 12 because no relevant data were available in Exam 11. The genotyping was done in 1702 individuals using 399 microsatellite markers on the 22 autosomal chromosomes. The allele frequencies of the markers and the sex-specific genetic maps were provided by the GAW13. The number of affected individuals for the four phenotype definitions (cross-sectional, lifetime ≥ 1, lifetime ≥ 2, lifetime ≥ 3) varied as follows: (255, 898, 713, 545) for hypertension, (185, 512, 384, 304) for obesity, (341, 597, 314, 182) for hyperglycemia, (228, 656, 348, 208) for hypertriglyceridemia, (522, 1046, 700, 482) for low HDL cholesterol, and (147, 699) for the metabolic syndrome (only cross-sectional and lifetime ≥ 1 were applicable).