Methods

Subjects

The FHS is a multicenter, population-based study designed to identify and evaluate genetic and nongenetic determinants of CHD, preclinical atherosclerosis, and cardiovascular disease risk factors. A description of the methods and design was previously published.⁹ Families in the study were chosen either at random (random group) or on the basis of higher-than-expected risk of CHD (high-risk group) from previously established population-based cohort studies. The high-risk group was defined on the basis of a family-risk score, which reflects a comparison of the family's age- and sex-specific incidence of CHD with that expected in the general population.¹⁰ As previously described, 566 families were selected on the basis of a higher-than-expected risk of CHD, and 588 were randomly selected. To reduce the locus heterogeneity, this sample was limited to Caucasians from the US.

Genotyping

Genotype data on 387 autosomal short-tandem-repeat polymorphisms were provided by the NHLBI Mammalian Genotyping Service at Marshfield, WI, USA. The data reported here are based on an initial genome scan that included 508 of the larger white families from the random and high-risk groups, of whom 2662 subjects had both genotyping and data on hostility phenotypes. The number of individuals per family with hostility scores ranged from 2 to 42, with an average of 7.4 individuals per family having phenotypic data. FHS colleagues at Washington University performed a simulation to estimate the power of variance component linkage analyses to identify quantitative trait loci (QTL) using the FHS pedigree structures. Based on 100 replicates in this simulation, a variance component analysis of the 3000 MGS genotyped individuals in FHS can achieve 80% power to detect a locus accounting for 12% heritability at a nominal alpha level of 0.05.

Hostility

The measure of hostility in this study consisted of three subscales of the Cook and Medley Hostility Scale:^11,12 cynicism, hostile affect, and aggressive responses, chosen because of their demonstrated ability to predict early mortality in a prospective cohort.¹¹

Statistical methods

We calculated the standardized residuals of hostility score for each gender, using the linear regression model in which age and educational levels were included. Residuals from these models were used in the subsequent genetic analysis.

Genome scans were performed using variance component linkage analysis as implemented by GENEHUNTER2.^13,14 Multipoint analysis was performed with genetic variance modeled as additive polygenic and QTL variance.

Results

There were 1241 men and 1421 women, and the average age was 51 years. The majority of subjects had more than a high school education. The results of the genome scan are listed in Table 1. Given the possibility that a complex trait such as hostility would involve multiple genes, rather than a single major gene, we have listed the results for all positions with a LOD score exceeding 1.0, to facilitate replication studies by other investigators.

Table 1 - Genome scan for hostility. LOD scores >1 for at least 1 scale.

Full table

The highest LOD score for the total hostility score was 1.77 (at 114.6 cM on chromosome 17). For the individual subscales, a LOD score of 1.97 on chromosome 12 was seen for the cynicism subscale, a score of 1.88 on chromosome 11 for the hostile affect subscale, and a score of 1.79 on chromosome 5 for the aggressive behavior subscale. Interestingly, at each of these locations, the other subscales showed LOD scores of zero. The heritability estimates were 0.268, 0.275, 0.248, and 0.326 for the aggressive behavior, cynicism, hostile affect, and summary hostility score, respectively.

The 5HTTLPR polymorphism of the serotonin transporter gene promoter region has been associated with serotonin function¹⁵ and serotonin has been implicated in aggressive behavior.¹⁶ However, we found little evidence for linkage at this site in our analyses (LOD scores <0.35).

Discussion

The genome scan in this cohort did not find significant linkage for total hostility or any of the three subscales. Although our earlier analyses found higher familial resemblance (heritability) for hostility than the present analyses,³ they were calculated solely on nuclear family members, a method that determines heredity by comparing the correlations between biologically related family members and nonrelated family members (spouses), reflecting shared environmental as well as genetic factors.

It is possible that no significant linkage was found because the familial resemblance reported in our earlier work was attributable to environmental as well as genetic factors. It is also possible that variance in hostility is explained by multiple genes rather than a single locus, or that it results from gene/environment interactions that were not measured in this study.

References

1. Knox SS et al. Am J Cardiol 1998; 82: 1192–1196. | Article | PubMed |
2. Knox SS et al. Am J Cardiol 2000; 86: 1089–1096. | Article |
3. Weidner G et al. Psychosom Med 2000; 62: 197–204. | PubMed |
4. Carmelli D et al. J Soc Behav Pers 1990; 5: 117–133.
5. Pederson NL et al. Psychosom Med 1989; 51: 428–440. | PubMed |
6. Rose RJ. J Pers Soc Psychol 1988; 55: 302–311. | Article | PubMed |
7. Smith TW et al. Psychosom Med 1991; 53: 684–692. | PubMed |
8. Matthews KA et al. Health Psychol 1992; 11: 317–323. | Article | PubMed |
9. Higgins M, et al., for the NHLBI Family Heart Study Investigators. Am J Epidemiol 1996; 143: 1219–1228. | PubMed | ISI | ChemPort |
10. Hunt SC et al. J Chronic Dis 1986; 39: 809–821. | PubMed |
11. Barefoot JC et al. Psychosom Med 1989; 51: 46–57. | PubMed |
12. Cook W, Medley D. Proposed hostility and pharisaic-virtue scales for MMPI. J Appl Psychol 1954; 38: 414–418.
13. Kruglyak L et al. Am J Hum Genet 1996; 58: 1347–1363. | PubMed | ISI | ChemPort |
14. Pratt SC et al. Am J Hum Genet 2000; 66: 1153–1157. | Article | PubMed | ISI | ChemPort |
15. Williams RB et al. Psychosom Med 2001; 63: 300–305. | PubMed |
16. Staner L, Mendlewicz J. Heredity and role of serotonin in aggressive impulsive behavior. Encephale 1998; 24: 355–364. | PubMed |

Acknowledgements

Support to this work was partially provided by the National Heart, Lung, and Blood Institute cooperative agreement grants U01 HL56563, U01 HL56564, U01 HL56565, U01 HL56566, U01 HL56567, U01 HL56568, and U01 HL56569. This paper is presented on behalf of the investigators of the NHLBI Family Heart Study. The participating institutions and principal staff of the study are as follows: Forsyth County/University of North Carolina/Wake Forest University: Gerardo Heiss, Stephen Rich, Greg Evans; James Pankow; HA Tyroler, Jeannette T Bensen, Catherine Paton, Delilah Posey, and Amy Haire; University of Minnesota Field Center: Donna K Arnett, Aaron R Folsom, Larry Atwood, James Peacock, and Greg Feitl; Boston University/Framingham Field Center: R Curtis Ellison, Richard H Myers, Yuqing Zhang, Andrew G Bostom, Luc Djoussé, Jemma B Wilk, and Greta Lee Splansky; University of Utah Field Center: Steven C Hunt, Roger R Williams (deceased), Paul N Hopkins, Hilary Coon and Jan Skuppin; Coordinating Center, Washington University, St Louis: Michael A Province, DC Rao, Ingrid B Borecki, Yuling Hong, Mary Feitosa, Jeanne Cashman, and Avril Adelman; Central Biochemistry Laboratory, University of Minnesota: John H Eckfeldt, Catherine Leiendecker-Foster, Michael Y Tsai, and Greg Rynders; Central Molecular Laboratory, University of Utah: Mark F Leppert, Jean-Marc Lalouel, Tena Varvil, Lisa Baird; National Heart, Lung, & Blood Institute—Project Office: Phyliss Sholinsky, Millicent Higgins (retired), Jacob Keller (retired), Sarah Knox, and Lorraine Silsbee.