Genomic survey of bipolar illness in the NIMH genetics initiative pedigrees: A preliminary report

Abstract

Four sites collaborated with the NIMH to develop a resource for the genetic study of bipolar (BP) illness. Common methods of ascertainment and assessment were developed in 1989. A series of families with a bipolar I (BPI) proband and at least one BPI or schizoaffective, bipolar type (SA/BP) first-degree relative has been studied. We now report initial data from a genomic survey with an average intermarker interval of 10 cM on 540 subjects from 97 families. This is the largest commonly ascertained and assessed linkage sample for bipolar illness reported to date; it includes 232 subjects with BPI, 32 SA/BP, 72 bipolar II (BPII), and 88 unipolar, recurrent (UPR). Nonparametric methods of analysis were employed, with all sites using affected sib pair analysis. The strongest findings thus far appear to be on chromosomes 1, 6, 7, 10, 16, and 22. Support has also been found for some previously reported linkages, including 21q and possibly Xq26. All these areas (as well as others) will be followed up with additional markers and further analyses. No locus tested thus far meets stringent criteria for an initial finding of significant linkage. Am. J. Med. Genet. 74:227-237, 1997. © 1997 Wiley-Liss, Inc.KEY WORDS: bipolar affective disorder; genetics; linkage; genomic survey; nonparametric analysis INTRODUCTIONBipolar affective disorder (BP) is a disabling condition involving dysregulation of multiple physiologic functions, including mood, appetite, sleep, and activity [Goodwin and Jamison, 1990]. It occurs in about 1% of the population, with usual onset in young adulthood. With appropriate management the condition is substantially treatment-responsive, but episodes tend to recur throughout life. This condition has long been observed to aggregate within families [Nurnberger et al., 1994b]. Twin and adoption studies suggest significant heritable risk factors [Bertelsen et al., 1977;Mendlewicz and Rainer, 1977]. The genetics of BP illness is complex, with segregation analyses generally not consistent with single major locus inheritance [Nurnberger et al., 1994b]. No pathognomonic biochemical abnormality is currently known to be present, and diagnosis is based on clinical history and presentation.Following the successful identification of linkage of Huntington disease to markers on chromosome 4 [Gusella et al., 1983], the interest of investigators in psychiatric genetics moved toward the application of molecular methods to the major psychiatric disorders. The paradigm for Mendelian disorders at that time was the identification of single large pedigrees with multiple cases of illness over several generations, and analysis of restriction fragment length polymorphism (RFLP) variation within the pedigree using the LOD score method. Egeland et al. [1987] reported linkage between BP and markers on chromosome 11p15 in a large Amish family. Subsequent studies in other samples, however, did not confirm this finding [DeteraWadleigh et al., 1987;Hodgkinson et al., 1987], and a later analysis in the same family, with additional clinical i...

A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19

“…If there is significant heterogeneity, this could explain the failure of genome screens of large cohorts of smaller sized pedigrees 13,34 to identify loci that meet the criteria for an initial finding of significant linkage. This may be due to the presence of multiple independently segregating susceptibility loci.…”

A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22

“…In an attempt to examine these results in an independent sample, we examined 57 families from the NIMH Bipolar Disorder Genetics Initiative sample (21). This is a subset of the larger NIMH family set, which was selected based on size and informativeness of pedigrees.…”

“…These 57 families included 345 subjects with the following diagnoses: 169 with bipolar I disorder, 36 with bipolar II disorder, and 45 with recurrent major depression. Ascertainment and diagnostic methods for these families have been described elsewhere (21). dinucleotide repeat markers from the Genethon map (23).…”

A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q

“…Clearly the number of possible susceptibility loci identified to date provide strong evidence that bipolar disorder is multigenic and subject to genetic heterogeneity. If there is significant heterogeneity, this could explain the failure of genome screens of large cohorts of smaller-sized pedigrees 14,39 to identify loci that meet the criteria for a initial finding of significant linkage, due to multiple independently segregating susceptibility loci. Conversely, genome screens of large multigenerational pedigrees have provided the most compelling evidence for linkage of bipolar disorder to a locus.…”