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Genomewide Linkage Analysis of Weight Change in the Framingham Heart Study

National Heart, Lung, and Blood Institute’s Framingham Heart Study (C.S.F., N.L.H.-C., R.S.V., J.M.M., R.B.D., L.D.A.), Framingham, Massachusetts 01702; National Heart, Lung, and Blood Institute (C.S.F.), Bethesda, Maryland 20892; Department of Endocrinology, Hypertension, and Metabolism, Brigham and Women’s Hospital and Harvard Medical School (C.S.F.), Boston, Massachusetts 02115; and Department of Neurology (N.L.H.-C., L.D.A.), Division of General Internal Medicine (J.M.M.), Division of Cardiology (R.S.V.), and Department of Mathematics and Statistics (R.B.D.), Boston University School of Medicine, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Dr. Caroline S. Fox, M.D., MPH, 73 Mount Wayte Avenue, Suite 2, Framingham, Massachusetts 01702. E-mail: foxca{at}nhlbi.nih.gov.

Background: Weight gain adversely affects blood pressure, lipids, and glycemia. The genetic contribution to weight change is unknown.

Methods: Variance components linkage analysis using microsatellites was performed on 336 families from the Framingham Heart Study offspring cohort, using a 10-cM genome-wide linkage analysis. We evaluated linkage to two traits: short-term (8-yr) weight change and long-term (up to 24-yr) weight change. Models were adjusted for age, age squared, baseline weight, smoking status, and menopausal status.

Results: Mean short-term weight change ranged from 1.4–3.8 kg, and mean long-term weight change was 7.7 kg. The heritability of long-term weight change was 0.24; weight change was minimally heritable among younger individuals and over shorter follow-up intervals. We found significant evidence for linkage for long-term weight change, with a peak LOD score of 3.10 on chromosome 20 at 63.7 cM (nearest marker, D20S481). We also found suggestive evidence for linkage on chromosome 1 at 239.7 cM (LOD score, 2.28; nearest marker, D1S1644).

Conclusion: Long-term weight change is heritable, and evidence for linkage exists on chromosomes 1 and 20. Potential candidate genes include MC3R, ASIP, AGT, and HSD11B1. Additional research is necessary to uncover the genetic underpinnings of weight change that might contribute to associated adverse metabolic profiles.