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A Linkage Study of Bipolar Illness
Wade H. Berrettini, MD, PhD;
Thomas N Ferraro, PhD;
Lynn R. Goldin, PhD;
Sevilla D. Detera-Wadleigh, PhD;
Henry Choi;
David Muniec;
Juliet J. Guroff, MSW;
Diane M. Kazuba;
John I. Nurnberger, Jr, MD, PhD;
Wang-Ting Hsieh, PhD;
Margret R. Hoehe, MD;
Elliot S. Gershon, MD
Arch Gen Psychiatry. 1997;54(1):27-35.
Abstract
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Background
Although genetic epidemiological studies of bipolar (BP) illness are consistent with a heritable component, inherited risk factors remain unknown. The goal of the present study is to describe the localization of BP susceptibility loci through linkage strategies, including a genome-wide search.
Methods
A linkage study of 22 BP families has been performed. These BP families include almost 400 persons, 173 of whom have been diagnosed as having BP I, schizoaffective, BP II with major depression, or recurrent unipolar illness. Using an autosomal dominant disease model with 85% or 50% age-dependent penetrance, and a recessive model with 85% penetrance, linkage analyses were performed assuming a narrow (BP and schizoaffective) or a broad (BP, schizoaffective, or unipolar) definition of the BP spectrum. Affected sibling pairs and affected pedigree member analyses were performed when positive lod scores were observed in multiple pedigrees. The present article describes linkage analusis of 310 DNA markers on chromosomes 1, 5p, 6, 8, 10q, 11q, and 12 to 18.
Results
None of the loci examined disclosed compelling evidence for linkage using lod score analyses. Modelindependent analysis by multilocus affected pedigree member method in the pericentromeric chromosome 18 region disclosed statistically significant evidence (P<.0001) for a BP susceptibility gene in this region. Multilocus analysis by affected sibling pair method also disclosed evidence for linkage (P<.00008).
Conclusions
Our results imply that a BP susceptibility gene exists near the centromere of chromosome 18. Confirmation of this finding (by independent investigators studying different pedigrees) has been published, suggesting that a valid BP disease linkage may have been discovered.
Author Affiliations
From the Department of Psychiatry and Human Behavior, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa (Drs Berrettini and Ferraro and Mr Choi); the Clinical Neurogenetics Branch, National Institute of Mental Health, Bethesda, Md (Drs Goldin, Detera-Wadleigh, Hsieh, Hoehe, and Gershon, Mr Muniec, and Mss Guroff and Kazuba); and the Institute for Psychiatric Research, Department of Psychiatry, Indiana University, Indianapolis (Dr Nurnberger). Dr Hsieh is now with Abbott Research Laboratories, North Chicago, Ill, and Dr Hoehe is with the Max Delbruck Center of Molecular Medicine, Berlin, Germany.
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