Juliet J. Guroff

Initial genome scan of the nimh genetics initiative bipolar pedigrees: Chromosomes 1, 6, 8, 10, and 12

A report on an initial genome screen on 540 individuals in 97 families was collected as part of the NIMH Genetics Initiative on Bipolar Disorder. Families were ascertained to be informative for genetic linkage and underwent a common ascertainment and assessment protocol at four clinical sites. The sample was genotyped for 65 highly polymorphic markers from chromosomes 1, 6, 8, 10, and 12. The average intermarker interval was 16 cM. Genotypic data was analyzed using affected sib pair, multipoint affected sib pair, and pedigree analysis methods. Multipoint methods gave lod scores of approximately two on chromosomes 1, 6, and 10. The peak lod score on chromosome 6 occurred at the end of the q-arm, at some distance from the 6p24-22 area previously implicated for schizophrenia. We are currently genotyping additional markers to reduce the intermarker interval around the signals. The interpretation of results from a genome screen of a complex disorder and the problem of achieving a balance between detecting false positive results and the ability to detect genes of modest effect are discussed.

Genomic Survey of Bipolar Illness in the NIMH Genetics Initiative Pedigrees: A Preliminary Report

NIMH Genetics Initiative Bipolar Group: John I. Nurnberger, Jr.* (Chair), J. Raymond DePaulo,Elliot S. Gershon, Theodore Reich, Mary C. Blehar, and collaborators from Indiana University(Howard J. Edenberg, Tatiana Foroud, Marvin Miller, Elizabeth Bowman, Aimee Mayeda, N. LeelaRau, Carrie Smiley, and P. Michael Conneally), Johns Hopkins University (Francis Mc-Mahon, Deborah Meyers, Sylvia Simpson, Melvin McInnis, and O. Colin Stine), NIMH IntramuralResearch Program (Sevilla Detera-Wadleigh, Lynn Goldin, Juliet Guroff, Elizabeth Max-well, Diane Kazuba, Pablo V. Gejman, Judith Badner, and Alan Sanders), and WashingtonUniversity of St. Louis (John Rice, Laura Bierut, and Alison Goate).Four sites collaborated with the NIMH todevelop a resource for the genetic study ofbipolar (BP) illness. Common methods of as-certainment and assessment were devel-oped in 1989. A series of families with a bi-polar I (BPI) proband and at least one BPIor schizoaffective, bipolar type (SA/BP)first-degree relative has been studied. Wenow report initial data from a genomic sur-vey with an average intermarker interval of10 cM on 540 subjects from 97 families. Thisis the largest commonly ascertained and as-sessed linkage sample for bipolar illness re-ported to date; it includes 232 subjects withBPI, 32 SA/BP, 72 bipolar II (BPII), and 88unipolar, recurrent (UPR). Nonparametricmethods of analysis were employed, with allsites using affected sib pair analysis. Thestrongest findings thus far appear to be onchromosomes 1, 6, 7, 10, 16, and 22. Supporthas also been found for some previously re-ported linkages, including 21q and possiblyXq26. All these areas (as well as others) willbe followed up with additional markers andfurther analyses. No locus tested thus farmeets stringent criteria for an initial find-ing of significant linkage. Am. J. Med. Genet.74:227–237, 1997.

Initial genome screen for bipolar disorder in the NIMH genetics initiative pedigrees: Chromosomes 2, 11, 13, 14, and X

We report on an initial genome screen of 540 individuals from 97 families collected as part of the NIMH Genetics Initiative Bipolar Group. Among the individuals studied, 232 were diagnosed with bipolar (BP) I, 72 with BPII, 88 with major depressive disorder-recurrent type (UPR), and 32 with schizoaffective disorder, bipolar type (SA/BP). A total of 53 markers on chromosomes 2, 11, 13, 14, and X (average spacing: 11.5 cM) were studied at Johns Hopkins University. Tests for linkage were performed using nonparametric affected sib-pair and whole pedigree methods with three definitions of affected status. Three regions of interest were identified (13q14-32, Xp22, and Xq26-28). On chromosomes 2, 11, and 14, a disease locus with relative risk lambda(i) = 1.5 could be excluded in <10% of the genetic distance studied, while a locus conferring lambda(i) = 3 or greater could be excluded across at least 96%. The autosomal region that could not be excluded even with lambda(i) = 5 was near 13q14-32. In this region, two-point affected sib-pair analyses revealed a pair of consecutive loci with excess sharing (P < 0.05) and a multipoint affected sib-pair LOD score of 1.12. On the X chromosome, nonparametric multipoint affected sib-pair analyses revealed peak total LOD scores of 0.94 on Xp22 and 1.34 on Xq26-28. A locus linked to the markers in Xp22 would have lambda(i) = 3.6 in affected brother-brother pairs, while a locus linked to the markers in Xq26-28 would have lambda(i) > 1.9 in affected sister-sister pairs. The results on 13q14-32, Xp22, and Xq26-28 suggest areas of interest for further studies.

Behavioral, biochemical and neuroendocrine responses to amphetamine in normal twins and ‘well-state’ bipolar patients ☆

An i.v. injection of dextroamphetamine (0.3 mgm/kg) was given to 13 pairs of normal monozygotic twins, three pairs of normal dizygotic twins and 11 patients with bipolar affective disorder in remission and off medications. Behavioral excitation in response to amphetamine was highly correlated in monozygotic twins; it was predicted by the baseline variables of high plasma MHPG, low serum prolactin and low pulse; it correlated with a rise in cortisol; and it was not correlated with plasma amphetamine level. Pre-infusion baseline MHPG and growth hormone and prolactin responses to amphetamine also were concordant in twins. Plasma amphetamine level, pulse and blood pressure and cortisol responses were not concordant, suggesting significant environmental influences. Haloperidol pretreatment in one pair of twins abolished the excitation response but did not reduce increases in cortisol and growth hormone. This suggests a role for dopamine in the excitation response but predominant serotonergic and noradrenergic mediation of the hormonal responses. None of the responses or baseline measures distinguished patients from controls. Thus, no consistently altered sensitivity to monoaminergic stimulation by amphetamine in bipolar affective disorder was demonstrated in this study. This is one of the first reports of familial (possibly genetic) variation in a psychostimulant drug response in man. The responses identified as concordant may be useful in characterizing other pathologic conditions.

Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees

As part of a four-center NIMH Genetics Initiative on Bipolar Disorder, a genome screen using 365 markers was performed on 540 DNAs from 97 families, enriched for affected relative pairs. This is the largest uniformly ascertained and assessed linkage sample for this disease, and includes 232 subjects diagnosed with bipolar I (BPI), 32 with schizo-affective, bipolar type (SABP), 72 with bipolar II (BPII), and 88 with unipolar recurrent depression (UPR). A hierarchical set of definitions of affected status was examined. Under Model I, affected individuals were those with a diagnosis of BPI or SABP, Model II included as affected those fitting Model I plus BPII, and Model III included those fitting Model II plus UPR. This data set was previously analyzed using primarily affected sib pair methods. We report the results of nonparametric linkage analyses of the extended pedigree structure using the program Genehunter Plus. The strongest finding was a lod score of 2.5 obtained on chromosome 10 near the marker D10S1423 with diagnosis as defined under Model II. This region has been previously implicated in genome-wide studies of schizophrenia and bipolar disorder. Other chromosomal regions with lod scores over 1.50 for at least one Model Included chromosomes 8 (Model III), 16 (Model III), and 20 (Model I). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:18-23, 2000

Validation of criteria for major depression through controlled family study

As compared with depressed relatives of normals, depressed relatives of affective patients are more likely to have severe impairment or incapacitation in their major life role when depressed, and more likely to suffer multiple episodes. These findings suggest that among major depressions, these clinical criteria may usefully identify cases with a familial, possibly genetic, vulnerability.

A family study of rapid-cycling bipolar illness

Twenty-nine out of 195 bipolar/episodic schizoaffective patients were judged to be rapid-cyclers (15%). Twenty-five of the 29 were female (86%). The age-corrected morbid risk for major affective disorder was 23.5% in 179 relatives of rapid-cyclers and 31.0% in 189 relatives of matched non-rapid cyclers (chi 2 = 2.6, NS). The prevalence of rapid-cycling itself was also not different in the two groups of relatives. Rapid-cycling thus appears to arise from factors which are separable from the genetic vulnerability to bipolar illness and which do not lead to aggregation within families.

A bipolar pedigree series for genomic mapping of disease genes: Diagnostic and analytic considerations

Twenty-one multiplex bipolar (BP) families, suitable for linkage studies, are described. The families include 365 informative persons (whose genotypes can be determined from available DNA samples), 154 of whom have BP, schizoaffective or recurrent unipolar diagnoses. The power of such a series to detect linkage is estimated through simulations under assumptions concerning the inheritance of BP illness, the genetic distances between the illness locus and markers, and marker heterozygosity. It is concluded that this series has greater than 50% power to detect linkage when only 25% of the families are linked to the locus under study. This paper is intended to serve as an introduction to a systematic genomic search for genes causing vulnerability to BP disease among these families.

Intravenous GABA administration is anxiogenic in man

Seven persons (three normal volunteers and four euthymic bipolar patients) received one to four doses of gamma-aminobutyric acid (GABA) intravenously. All subjects reported dysphoria, and their mood disturbance scores on the Profile of Mood States were significantly increased in a dose-related fashion. Placebo infusions did not produce similar responses. Mood disturbance was accompanied by a dose-related increase in pulse and blood pressure.

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

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.