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Late-onset Alzheimer disease (LOAD) is a complex genetic disorder. Although genes involved in early-onset forms were discovered more than a decade ago, LOAD research has only been able to point out small effect loci, with the exception of APOE. We mapped the gene predisposing to LOAD in an extended inbred family coming from a genetically isolated region (24 sampled individuals, 12 of whom are affected), completing a genome-wide screen with an Affymetrix10 K single nucleotide polymorphism microarray. Genotyping results were evaluated under model-dependent (dominant and recessive) and model-free analysis. We obtained a maximum nonparametric linkage score of 3.24 (P=0.00006) on chromosome 8p22-p21.2. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) under a recessive model (HLOD=3.04). When we compared the results of the model-dependent analysis, a higher score was obtained in the recessive model (3.04) than in the dominant model (1.0). This is a new locus identified in LOAD, in chromosome 8p22-p21.2 and encompassing several candidate genes, among them CLU and PPP3CC that were excluded by sequencing. The finding of a recessive model of inheritance, consistent with the assumption of inbreeding as a morbidity factor in this population, supports the notion of a role of recessive genes in LOAD., ((C) 2012 Lippincott Williams & Wilkins, Inc.)

Common hereditary neurodevelopmental disorders such as autism, bipolar disorder, and schizophrenia are most likely both genetically multifactorial and heterogeneous. Because of these characteristics traditional methods for genetic analysis fail when applied to such diseases. To address the problem we propose a novel probabilistic framework that combines the standard genetic linkage formalism with whole-genome molecular-interaction data to predict pathways or networks of interacting genes that contribute to common heritable disorders. We apply the model to three large genotype-phenotype data sets, identify a small number of significant candidate genes for autism (24), bipolar disorder (21), and schizophrenia (25), and predict a number of gene targets likely to be shared among the disorders.

We conducted a 9-cM genome scan in a large bipolar pedigree sample from the National Institute of Mental Health genetics initiative (1060 individuals from 154 multiplex families). We performed parametric and nonparametric analyses using both standard diagnostic models and comorbid conditions thought to identify phenotypic subtypes: psychosis, suicidal behavior, and panic disorder. Our strongest linkage signals (genome-wide significance) were observed on chromosomes 10q25, 10p12, 16q24, 16p13, and 16p12 using standard diagnostic models, and on 6q25 (suicidal behavior), 7q21 (panic disorder) and 16p12 (psychosis) using phenotypic subtypes. Several other regions were suggestive of linkage, including 1p13 (psychosis), 1p21 (psychosis), 1q44, 2q24 (suicidal behavior), 2p25 (psychosis), 4p16 (psychosis, suicidal behavior), 5p15, 6p25 (psychosis), 8p22 (psychosis), 8q24, 10q21, 10q25 (suicidal behavior), 10p11 (psychosis), 13q32 and 19p13 (psychosis). Over half the implicated regions were identified using phenotypic subtypes. Several regions - 1p, 1q, 6q, 8p, 13q and 16p - have been previously reported to be linked to bipolar disorder. Our results suggest that dissection of the disease phenotype can enrich the harvest of linkage signals and expedite the search for susceptibility genes. This is the first large-scale linkage scan of bipolar disorder to analyze simultaneously bipolar disorder, psychosis, suicidal behavior, and panic disorder.

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.

Manic-depressive illness is a common psychiatric disorder with complex etiology that likely involves multiple genes and non-genetic influences. The uncertain path to gene discovery has spurred considerable debate over genetic findings and gene-finding strategies. In this article, I review the main findings, with a focus on: (1) putative linked loci on chromosomes 1q31-32, 4p16, 6pter-p24, 10p14, 10q21-26, 12q23-24, 13q31-32, 18p11, 18q21-23, 21q22, 22q11-13, and Xq24-28; and (2) association studies with candidate genes, dynamic mutations, mitochondrial mutations, and chromosomal aberrations. Although no gene has been identified, promising findings are emerging. I then discuss the challenges and opportunities ahead, with special emphasis on gene-finding methods-in particular, questions pertaining to phenotype definition, linkage and association mapping, gene markers, sampling, study population, multigene systems, lessons from other disorders, animal models, and bioinformatics. The progress to date, together with rapid advances in genomics, analytical and computational methods, and bioinformatics, holds promise for new insights into the genetics of manic-depression, in the new millennium.

Evidence for linkage between bipolar affective disorder (BP) and 21q22 was first reported by our group in a single large pedigree with a lod score of 3.41 with the PFKL locus. In a subsequent study, with denser marker coverage in 40 multiplex BP pedigrees, we reported supporting evidence with a two-point lod score of 2.76 at the D21S1260 locus, about 6 cM proximal to PFKL. For cost-efficiency, the individuals genotyped in that study comprised a subset of our large pedigree sample. To augment our previous analysis, we now report a follow-up study including a larger sample set with an additional 331 typed individuals from the original 40 families, improved marker coverage, and an additional 16 pedigrees. The analysis of all 56 pedigrees (a total of 862 genotyped individuals vs. the 372 genotyped previously), the largest multigenerational BP pedigree sample reportedly analyzed to date, supports our previous results, with a two-point lod score of 3.56 with D21S1260. The 16 new pedigrees analyzed separately gave a maximum two-point lod score of 1.89 at D21S266, less than 1 cM proximal to D21S1260. Our results are consistent with a putative BP locus on 21q22., (Copyright 2001 Wiley-Liss, Inc.)

With the human DNA sequence nearing completion, the search for complex disease genes is gaining momentum, as is the debate over gene-finding strategies. This overview contrasts two pivotal methods: linkage analysis and association mapping. Linkage analysis has been used successfully to identify the genes underlying rare mendelian disorders. It has also played a role in attempts to map genes for common non-mendelian (also known as 'complex' or 'multifactorial') diseases such as psychiatric disorders. However, despite extensive efforts progress has been slow, marred by inconsistent or ambiguous results. Uncertainties about the utility of the linkage approach for complex genetic traits has spurred interest in association studies with candidate genes, as an alternate strategy. Recently, with the advent of new molecular tools, in particular high-density, single-nucleotide polymorphisms (SNPs) maps, it has been argued that, while linkage analysis may retain some role, genome-wide association studies with SNPs offer a superior strategy for unraveling genetic complexity. In this paper I review these issues, stressing the pros and cons of the various strategies. I propose that: (1) the uncertainties in association studies may have been underestimated; (2) neither method is sufficient or optimal; and (3) a joint linkage and association approach, together with genomic, statistical and computational advances, may have greater promise for understanding the genetic underpinnings of complex disorders in the new millennium.

Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22.3. Additional families showed little support for linkage to PFKL under homogeneity or heterogeneity, in that study. We have expanded on that analysis, with 31 microsatellite markers at an average marker spacing of

Bipolar affective disorder (BP) is a major neuropsychiatric disorder with high heritability and complex inheritance. Previously reported linkage between BP and DNA markers in the pericentromeric region of chromosome 18, with a parent-of-origin effect (linkage was present in pedigrees with paternal transmission and absent in pedigrees with exclusive maternal inheritance), has been a focus of interest in human genetics. We reexamined the evidence in one of the largest samples reported to date (1,013 genotyped individuals in 53 unilineal multiplex pedigrees), using 10 highly polymorphic markers and a range of parametric and nonparametric analyses. There was no evidence for significant linkage between BP and chromosome 18 pericentromeric markers in the sample as a whole, nor was there evidence for significant parent-of-origin effect (pedigrees with paternal transmission were not differentially linked to the implicated chromosomal region). Two-point LOD scores and single-locus sib-pair results gave some support for suggestive linkage, but this was not substantiated by multilocus analysis, and the results were further tempered by multiple test effects. We conclude that there is no compelling evidence for linkage between BP and chromosome 18 pericentromeric markers in this sample.

The history of linkage studies in bipolar affective disorder is a convoluted affair punctuated by upswings and setbacks, hope and skepticism. Advances in genomics and statistical techniques, and the availability of well-characterized clinical samples, have bolstered the search for disease genes, leading to a new crop of findings. Indeed, recent reports of putative loci on chromosomes 18, 21, X, 4, 6, 13 and 15 have rekindled a sense of optimism. The new findings are reviewed and scrutinized, with implications for future research.

Despite initial setbacks, linkage studies with DNA markers continue to occupy center stage in psychiatric research. Advances in molecular and statistical techniques have revived the search for disease genes, leading to a new harvest of findings. Most interest in recent years has focused on potential linkages between schizophrenia and chromosomes X-Y (the pseudoautosomal region) and 22q12-13.1, and between bipolar affective disorder and chromosomes 18 (pericentromeric region) and 21q22.3. This article provides a critical evaluation of theses studies, with implications for future research. Concerns over earlier linkage trials make this scrutiny current and topical.

The search for complex disease genes is gaining momentum. Recent guidelines for expediting this effort, such as "intelligent" genome scanning and statistical criteria for detecting weak signals indicative of linkage, are discussed, with special reference to psychiatric disorders.

The hypothesis that chromosomal region Xq27-28 harbours a gene for manic-depression has been a focus of interest in human genetics. X-linked inheritance of manic depressive illness has been re-examined in 3 multigeneration Israeli kindreds. Extension and re-evaluation of pedigree data, including new individuals, diagnostic follow-up, and analysis with DNA markers, shows greatly diminished support for linkage to Xq28. The peak lod scores in two of the pedigrees have dropped several lod units to clearly negative values at the RCP-F8-G6PD gene cluster. On the other hand, positive lod scores (Zmax = 2.09) are sustained in another pedigree at the same map location. None of the pedigrees show linkage to more proximal markers, including the Xq27 locus DXS98. Our analysis underscores the uncertainties in studying complex disorders.

Genetic-epidemiological data and linkage studies with chromosomal markers are reviewed from the vantage point of X-linked inheritance. The results overall suggest that a gene predisposing to manic depression (bipolar affective illness) localized on the X-chromosome may exist in a subgroup of bipolar cases. However, in light of conflicting findings and methodological uncertainties in studying a disorder with unclear phenotype and complex inheritance, this issue is not yet closed. Additional research, including new linkage data and extension and re-evaluation of published data, is required to further our understanding of this intriguing hypothesis.

The relationship between schizophrenic 'spectrum' disorders and affective illness was studied in the nuclear families of 90 chronic schizophrenic probands. An increased risk of schizophrenia and related disorders was demonstrated among the first-degree relatives of probands with a family history of major affective disorders. Conversely, relatives of probands with a family history of schizophrenic 'spectrum' disorders were at a greater risk of affective illness (major depression) than relatives of probands with no family history. These results lend support to the notion that a subset of affective disorders is associated with the liability to schizophrenia.

Advances in genetic linkage strategies, including techniques of molecular genetics, augur well for the discovery of disease-related genes in mental disorders. Recent studies showing linkage of chromosomal loci to bipolar affective illness and schizophrenia attest to the potential in the 'new genetics'. However, the failure to replicate some of the early findings has led to calls for re-evaluation of the methodology in psychiatric research. Problems in studying complex (psychiatric) disorders include diagnostic uncertainties, unclear mode of transmission, aetiological heterogeneity, cohort effects, and assortative mating. Knowing the potential pitfalls in linkage analysis of mental illness should avert spurious findings and will increase the prospects of success.

Genetic linkage studies have opened new vistas for behavioral and psychiatric genetics. However, phenotypic diversity and diagnostic uncertainties can lead to spurious linkage findings. A method of analysis is proposed that takes these factors into account. When applied to manic-depressive disease, the results indicate that previous evidence for a major gene localized on the distal long arm of the X-chromosome cannot be ascribed to phenotypic uncertainties and misclassifications, i.e., a type I error. Although the lod score (the logarithm of odds) favoring linkage is reduced with the more restrictive clinical definitions of the phenotype, it remains significant nonetheless. Thus, the linkage finding is robust over a range of phenotypic patterns and presumed phenocopy frequencies. The results also suggest that the X-linked phenotype is a particularly severe form of manic depression characterized by early onset, high familial prevalence of the bipolar form, and high recurrence rate of major depression. These findings may have important implications for the design and interpretation of genetic linkage studies and for refining diagnostic techniques in mental disorders.

The search for genetic markers is a powerful strategy in psychiatric genetics. The present article examines four areas relevant to discrepancies among X-linkage studies in bipolar affective disorder. These are questions of ascertainment, analytic methods, the X-chromosome map and genetic heterogeneity. The following conclusions are reached: (a) Positive linkage findings cannot be attributed to ascertainment bias or association between affective illness and colorblindness. (b) The possibility that falsely positive linkage results were obtained by using inappropriate analytic methods is ruled out. (c) Reported linkages of bipolar illness to colorblind and G6PD loci are compatible with known map distances between X-chromosome loci. Linkage to the Xg antigen remains uncertain. (d) The discrepancy among the various data sets on affective illness and colorblindness is best explained by significant linkage heterogeneity among pedigrees informative for the two traits.

Data from a family study of bipolar affective illness in New York (1968-1972) are reexamined from the vantage point of X-linked dominant inheritance and genetic heterogeneity. For comparison, published data from a similar study in Bethesda (1974-1979) and from a literature summary are also re-analyzed. The New York data support the presence of a change in rates of affective illness over time (secular trend), with a substantial increase in risk at early ages for individuals born after 1920. Hence, risk ratios by sex of proband (male vs female) are calculated for each type of relative, thereby controlling simultaneously for generation and sex of relative. The risk ratios for all three studies are in the direction predicted by X-linkage. In addition, logistic regression is performed, incorporating the effects of generation, sex of relative, sex of proband, and X-linkage. In all three samples, the largest effect is due to X-linkage, which reaches statistical significance in the New York and literature summary samples. The results also suggest genetic heterogeneity, in that only a subgroup of bipolars carry the X-linked gene. Crude estimates predict that perhaps one-third of bipolars carry the X-linked gene. Analysis of the New York material also indicates that an X-linked subgroup may be associated with early onset (before 30 years old). These results are consistent with those from linkage analysis with markers on the long arm of the X chromosome.

Studies with X-chromosome markers in mental illness have been limited to the diagnostic concept of primary affective disorders. The present study is the first to our knowledge to demonstrate statistically measurable linkage between color blindness and manic-depressive illness in a family identified by a schizo-affective proband. Linkage data and lithium carbonate response in the proband suggest that the schizophreniform-affective spectrum in members of the pedigree may reflect a genetically distinct disorder. The use of a genetic marker as a heuristic diagnostic criterion in a subgroup of heredofamilial psychoses with unclear diagnostic boundaries is proposed.

It has been suggested that an X-linked dominant allele operates in the genetic transmission of bipolar (manic-depressive) illness. Linkage studies with X-chromosome markers have remained inconclusive, showing both positive and negative results. Some of the ambiguity may be attributed to imprecise analytic methods and genetic heterogeneity. In this report, recently published pedigree series are reanalysed for linkage using a systematic method of pedigree analysis (Liped 3) with an accurate age-of-onset correction. Linkage heterogeneity is assessed through a two-recombination fraction heterogeneity test suggested by Smith (1963). The results are as follows: (1) Close linkage of bipolar illness to colourblindness (deutan and protan) and glucose-6-phosphate dehydrogenase deficiency appears to be present in some pedigrees, with estimated recombination fractions of theta = 0.05 and 0.00, respectively; (2) Linkage with the Xg blood group cannot be supported. These results are consistent with known linkages on the X chromosome.