J. Raymond DePaulo

Combined Analysis from Eleven Linkage Studies of Bipolar Disorder Provides Strong Evidence of Susceptibility Loci on Chromosomes 6q and 8q

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

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.

Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: A pilot study

BACKGROUND Previous reports of ventricular and hippocampal volumes in patients with bipolar disorder (BP) have been inconsistent in their findings. One possibility is that volumetric abnormalities are determined by disease subtype. Prior evidence suggests that psychotic (PBP) and nonpsychotic (NPBP) forms of BP are two subtypes that might differ in pathophysiology. METHODS We investigated ventricular and hippocampal volumes in 38 adults with clearly defined PBP (n = 23) and NPBP subtypes, compared with 33 persons with schizophrenia (SZ) and 44 healthy community control subjects (HC). Ventricular and hippocampal volumes were reliably measured on high-resolution anatomic magnetic resonance imaging scans. We used a multivariate analysis of covariance to compare volumes across groups, covarying for total brain volume. Potential effects of BP illness features were explored, contrasting PBP and NPBP. RESULTS For ventricular but not hippocampal regions, we found significant volume difference in PBP but not NPBP compared with HC (p < .005). We also observed nonsignificantly smaller left hippocampal volumes in PBP versus HC. Schizophrenic subjects had significantly larger ventricular and smaller left hippocampal volumes than HC. CONCLUSIONS These results suggest that PBP but not NPBP is associated with increased ventricle volumes and a trend toward smaller left hippocampal volumes, as observed in SZ.

Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: Chromosomes 3, 5, 15, 16, 17, and 22

As part of the four-center NIMH Genetics Initiative on Bipolar Disorder we carried out a genomic scan of chromosomes 3, 5, 15, 16,17, and 22. Genotyping was performed on a set of 540 DNAs from 97 families, enriched for affected relative pairs and parents where available. We report here the results of the initial 74 markers that have been typed on this set of DNAs. The average distance between markers (theta) was 12.3 cM. Nonparametric analysis of excess allele sharing among affected sibling pairs used the SIBPAL program of the S.A.G.E. package to test three hierarchical models of affected status. D16S2619 gave some evidence of linkage to bipolar disorder, with P = 0.006 for Model II (in which bipolar 1, bipolar 2 and schizoaffective-bipolar type individuals are considered affected). Nearby markers also showed increased allele sharing. A second interesting region was toward the telomere of chromosome 5q, where D5S1456 and nearby markers showed increased allele sharing; for D5S1456, P = 0.05, 0.015 and 0.008 as the models of affected status become more broad. MOD score analysis also supported the possible presence of a susceptibility locus in this region of chromosome 5. A pair of adjacent markers on chromosome 3, D3S2405 and D3S3038, showed a modest increased allele sharing in the broad model. Several isolated markers had excess allele sharing at the P < 0.05 level under a single model. D15S217 showed a MOD score of 2.37 (P < 0.025). Multipoint analysis flagged the region of chromosome 22 around D22S533 as the most interesting. Thus, several regions showed modest evidence for linkage to bipolar disorder in this initial genomic scan of these chromosomes, including broad regions near previous reports of possible linkage.

Genome-wide scan of bipolar disorder in 65 pedigrees: Supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12

The purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parent of origin effect using several analytical methods. We identified 15 loci with nominally significant evidence for increased allele sharing among affected relative pairs. Eight of these regions, at 8q24, 18q22, 4q32, 13q12, 4q35, 10q26, 2p12, and 12q24, directly overlap with previously reported evidence of linkage to bipolar disorder. Five regions at 20p13, 2p22, 14q23, 9p13, and 1q41 are within several Mb of previously reported regions. We report our findings in rank order and the top five markers had an NPL>2.5. The peak finding in these regions were D8S256 at 8q24, NPL 3.13; D18S878 at 18q22, NPL 2.90; D4S1629 at 4q32, NPL 2.80; D2S99 at 2p12, NPL 2.54; and D13S1493 at 13q12, NPL 2.53. No locus produced statistically significant evidence for linkage at the genome-wide level. The parent of origin effect was studied and consistent with our previous findings, evidence for a locus on 18q22 was predominantly from families wherein the father or paternal lineage was affected. There was evidence consistent with paternal imprinting at the loci on 13q12 and 1q41.

Lateral ventricular enlargement associated with persistent unemployment and negative symptoms in both schizophrenia and bipolar disorder

Forty-six patients with schizophrenia or bipolar disorder and 46 individually matched normal volunteers underwent computed tomographic (CT) scans of the head. The ventricular-to-brain ratio was strongly associated with persistent unemployment and negative symptoms in both patient groups. Previous findings of relative lateral ventricular enlargement in a proportion of schizophrenic and bipolar patients were also replicated. Implications of the relationship between CT changes and chronic unemployment among the patients are discussed.

Symptomatic, familial, perinatal, and social correlates of computerized axial tomography (Cat) changes in schizophrenics and bipolars

Computerized axial tomography (CAT) scans were blindly examined, and lateral ventricular-to-brain ratios calculated in 19 schizophrenic and 27 bipolar patients, and in an equal number of individually matched normal controls. Family history, early development, past psychiatric history, and current functioning and symptomatology were analyzed for all patients. Lateral ventricular enlargement on CAT was found in a significant proportion of both patient groups. Patients with such enlargement tended to have greater numbers of negative symptoms and poorer premorbid adjustment, but did not differ regarding family history of psychiatric illness. A subgroup of schizophrenics with presumed early brain damage was identified. This group had more marked ventricular enlargement, a greater number of negative symptoms, and an earlier onset of illness.

Future of genetics of mood disorders research

This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.

Genomewide Significant Linkage to Recurrent, Early-Onset Major Depressive Disorder on Chromosome 15q

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele sharing in all possible affected relative pairs with the use of the Z(lr) statistic computed by the ALLEGRO program. A secondary logistic regression analysis considered the effect of the sex of the pair as a covariate. Genomewide significant linkage was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical genomewide P=.023). The linkage was not sex specific. No other suggestive or significant results were observed in the primary analysis. The secondary analysis produced three regions of suggestive linkage, but these results should be interpreted cautiously because they depended primarily on the small subsample of 42 male-male pairs. Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility to MDD.

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.