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The role of the LRP5gene in rare BMD‐related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5in our sample.

The role of the LRP5gene in rare BMD‐related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5in our sample.Introduction:Mutations in the low‐density lipoprotein receptor‐related protein 5(LRP5) gene have been implicated as the cause of multiple distinct BMD‐related rare Mendelian phenotypes. We sought to examine whether the LRP5gene contributes to the observed variation in peak BMD in the normal population.Materials and Methods:We genotyped 12 single nucleotide polymorphisms (SNPs) in LRP5using allele‐specific PCR and mass spectrometry methods. Linkage disequilibrium between the genotyped LRP5SNPs was measured. We tested for association between these SNPs and both hip and spine BMD (adjusted for age and body weight) in 1301 healthy premenopausal women who took part in a sibling pair study aimed at identifying the genes underlying peak bone mass. Our study used both population‐based (ANOVA) and family‐based (quantitative transmission disequilibrium test) association methodology.Results and Conclusions:The linkage disequilibrium pattern and haplotype block structure within the LRP5gene were consistent with that observed in other studies. Although significant evidence of association was found between LRP5SNPs and both hip and spine BMD, only a small proportion of the total variation in these phenotypes was accounted for. The genotyped SNPs accounted for ∼0.8% of the variation in femoral neck BMD and 1.1% of the variation in spine BMD. Results from our sample suggest that natural variation in and around LRP5is not a major contributor to the observed variability in peak BMD at either the femoral neck or lumbar spine in white women.

Smoking is a highly heritable, addictive disorder that commonly co-occurs with alcohol dependence. The purpose of this study is to perform a genomic screen for habitual smoking and comorbid habitual smoking and alcohol dependence in families from the Collaborative Study on the Genetics of Alcoholism (COGA). Subjects were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) to evaluate alcohol dependence and habitual smoking (smoking one pack per day or more for at least 6 months). Sixty seven multi-generational families with 154 independent sibling pairs affected with habitual smoking were genotyped in a screening sample. Analyses on 79 multi-generational families with 173 independent sibling pairs were repeated in a replication sample. Sibpair analyses were performed using ASPEX. Four chromosomal regions in the screening sample had increased allele sharing among sibling pairs for habitual smoking with a LOD score greater than 1 (chromosomes 5, 9, 11, and 21). The highest LOD score was on chromosome 9 (LOD = 2.02; allele sharing 58.9%). Four chromosomal regions also had modest evidence for linkage to the comorbid phenotype habitual smoking and alcohol dependence (chromosomes 1, 2, 11, 15); and the strongest finding was on chromosome 2 (LOD = 3.30; allele sharing 69.1%). Previously identified areas (chromosomes 1 and 7) implicated in the development of alcohol dependence in this same data set did not provide evidence for linkage to habitual smoking in the screening sample. In the replication data set, there continued to be increased allele sharing near peaks identified in the screening sample on chromosomes 2 and 9, but the results were modest. An area on chromosome 7, approximately 60 cM from a location previously identified in linkage analysis with alcohol dependence, had increased allele sharing for the comorbid habitual smoking and alcohol dependence. These data provide evidence of specific genetic regions involved in the development of habitual smoking and not alcohol dependence. Conversely, genetic regions that influence the development of alcohol dependence do not appear to contribute to the development of habitual smoking. Finally, there is also evidence of an area on chromosome 2 that may reflect a common genetic vulnerability locus to both habitual smoking and alcohol dependence. © 2003 Wiley-Liss, Inc.

Individuals at-risk for Huntington disease (HD), both HD gene carriers and nongene carriers, were recruited to determine whether psychological changes are detectable among clinically presymptomatic individuals who carry the HD allele. Each participant underwent genotyping to determine HD gene carrier status and a clinical assessment that included a quantified neurological examination and an abbreviated Minnesota Multiphasic Personality Inventory (MMPI): the Hypochondriasis, Depression, Psychasthenia, Neuroticism, Cynical Hostility, and Irritability Scales and the Harris Subscales of Depression. The results of the MMPI were evaluated for differences between nongene carriers (NGC) ( n =363), presymptomatic gene carriers (PSGC) ( n =149), and those with manifest HD (MHD) ( n =26). The overall multiple analysis of variance was not significant, indicating that there was no overall difference among the three groups. However, when subscales of the MMPI were examined individually, participants with manifest HD scored higher on the Psychasthenia scale (MHD vs. PSGC, P =0.005; MHD vs. NGC, P =0.03) and the Harris Depression subscale, Brooding (MHD vs. PSGC, P =0.0005; MHD vs. NGC, P =0.003). No significant correlation was found between the number of trinucleotide repeats on the disease-producing allele and any of the MMPI scales for the gene carriers, MHD or PSGC. These results verify the presence of psychological symptoms in the early phases of MHD but not in PSGC. Thus, further study of the behavioral and mood symptoms thought to accompany HD using measures designed specifically to detect depressive symptoms and changes in behavior specific to HD is warranted to delineate the timing of onset of the psychological symptoms.

Femoral structure contributes to bone strength at the proximal femur and predicts hip fracture risk independently of bone mass. Quantitative components of femoral structure are highly heritable traits. To identify genetic loci underlying variation in these structural phenotypes, we conducted an autosomal genome screen in 309 white sister pairs. Seven structural variables were measured from femoral radiographs and used in multipoint sib‐pair linkage analyses. Three chromosomal regions were identified with significant evidence of linkage (log10of the odds ratio [LOD] > 3.6) to at least one femoral structure phenotype. The maximum LOD score of 4.3 was obtained for femur neck axis length on chromosome 5q. Evidence of linkage to chromosome 4q was found with both femur neck axis length (LOD = 3.9) and midfemur width (LOD = 3.5). Significant evidence of linkage also was found to chromosome 17q, with a LOD score of 3.6 for femur head width. Two additional chromosomal regions 3q and 19p gave suggestive (LOD > 2.2) evidence of linkage with at least two of the structure phenotypes. Chromosome 3 showed evidence of linkage with pelvic axis length (LOD = 3.1), midfemur width (LOD = 2.8), and femur head width (LOD = 2.3), spanning a broad (60 cm) region of chromosome 3q. Linkage to chromosome 19 was supported by two phenotypes, femur neck axis length (LOD = 2.8) and femur head width (LOD = 2.8). This study is the first genome screen for loci underlying variation in femoral structure and represents an important step toward identifying genes contributing to the risk of osteoporotic hip fracture in the general population.

Femoral structure contributes to bone strength at the proximal femur and predicts hip fracture risk independently of bone mass. Quantitative components of femoral structure are highly heritable traits. To identify genetic loci underlying variation in these structural phenotypes, we conducted an autosomal genome screen in 309 white sister pairs. Seven structural variables were measured from femoral radiographs and used in multipoint sib‐pair linkage analyses. Three chromosomal regions were identified with significant evidence of linkage (log10of the odds ratio [LOD] > 3.6) to at least one femoral structure phenotype. The maximum LOD score of 4.3 was obtained for femur neck axis length on chromosome 5q. Evidence of linkage to chromosome 4q was found with both femur neck axis length (LOD = 3.9) and midfemur width (LOD = 3.5). Significant evidence of linkage also was found to chromosome 17q, with a LOD score of 3.6 for femur head width. Two additional chromosomal regions 3q and 19p gave suggestive (LOD > 2.2) evidence of linkage with at least two of the structure phenotypes. Chromosome 3 showed evidence of linkage with pelvic axis length (LOD = 3.1), midfemur width (LOD = 2.8), and femur head width (LOD = 2.3), spanning a broad (60 cm) region of chromosome 3q. Linkage to chromosome 19 was supported by two phenotypes, femur neck axis length (LOD = 2.8) and femur head width (LOD = 2.8). This study is the first genome screen for loci underlying variation in femoral structure and represents an important step toward identifying genes contributing to the risk of osteoporotic hip fracture in the general population.

Background: There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members.

A recent study showed an association between the dopamine D2 receptor gene (DRD2) and smoking. The purpose of this study was to determine if the familial transmission of smoking is linked to variation at the DRD2 locus in a genetically informative sample. Subjects were identified in alcohol treatment centers and their relatives were recruited for study. All subjects were interviewed to assess alcohol dependence, smoking habits, and psychiatric disorders. Two polymorphisms within the DRD2 gene were analyzed, including the TaqIA polymorphism. The sample consisted of 138 nuclear families with at least one offspring with habitual smoking, and analysis was by the transmission disequilibrium test (TDT), which avoids problems due to population stratification. There was no significant difference in the frequency between DRD2 alleles transmitted and not transmitted to habitual smokers. There also was no evidence for unequal transmission of DRD2 alleles for the phenotypes “ever smoker” or comorbid alcohol dependence and habitual smoking. This study does not support linkage of the DRD2 with smoking. Am. J. Med. Genet. 90:299–302, 2000. © 2000 Wiley-Liss, Inc.

BACKGROUND: The apolipoprotein E4 (APOE*4) allele is a major risk factor for the common forms of late-onset Alzheimer disease (AD), but does not account for all the genetic variation in late-onset AD; hence, other genetic markers must be examined. The D2 dopamine receptor (DRD2) A1 allele is associated with abnormal brain function and decreased DRD2s. These receptors are decreased in hippocampus and amygdala in AD, and allele frequencies may vary with age. OBJECTIVE: To study APOE and DRD2 genotypes in patients with AD and cognitively intact controls of varying ages. DESIGN: The DRD2 and APOE genotypes were examined in 832 unrelated white subjects, including 554 patients with AD (486 sporadic; 68 familial) and 278 controls. Logistic regressions tested Al allele effects on disease status and age, and DRD2 linkage with AD was investigated in 60 families with late-onset AD. SETTING: University medical centers. SUBJECTS: Patients (mean±SD age, 74.6±8.1 years; range, 52-98 years) had probable AD, according to standard consensus diagnostic criteria; controls (mean±SD age, 69.2±8.6 years; range, 50-93 years) were cognitively intact. MAIN OUTCOME MEASURES: Disease status, age, and DRD2 linkage with AD. RESULTS: No association between the DRD2 and APOE alleles was found, and the presence of the Al allele did not increase the risk for AD. There was also no evidence of linkage between DRD2 and AD. Age analyses, including both patients and controls, indicated a decrease in Al allele frequency with age. CONCLUSIONS: The Al allele does not contribute to AD risk, alone or in combination with the APOE*4 allele. The DRD2 Al allele frequencies decrease with age in both patients and controls. Thus, studies of DRD2 disease association need to control for age.

OBJECTIVE: To determine whether changes in motor function and reaction time are present in presymptomatic individuals carrying the Huntington disease (HD) allele. DESIGN: A case-control, double-blind study comparing asymptomatic at-risk subjects, with or without the HD allele, and subjects clinically determined to have early manifest HD. SETTING: The Department of Medical and Molecular Genetics at Indiana University School of Medicine, Indianapolis. PARTICIPANTS: We studied 383 patients at risk for HD. Each subject was asymptomatic by self-report. MEASURES: Genotype for the HD allele was determined by polymerase chain reaction testing. A battery of 8 physiological tests measuring speed of movement and reaction time was performed with a computer-driven system. RESULTS: Following neurologic examination, 17 of the 120 gene carriers (GCs) had symptoms sufficient for a clinical diagnosis of manifest HD. The remaining 103 GCs were designated presymptomatic GCs. When the non-GCs were compared with the presymptomatic GCs (1-way analysis of covariance and the Fisher protected t test), results on 3 of the 8 physiological tests—movement time, movement time with decision, and auditory reaction time—were different. Additionally, the number of trinucleotide (CAG) repeats significantly correlated with test performance for movement time with decision and visual reaction time with decision when both the entire group of GCs and the presymptomatic GCs alone were considered. CONCLUSION: These results suggest that subtle subclinical changes in motor function are present in presymptomatic individuals who have inherited the HD allele.

The Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy) loci have been reported to be on at least three chromosomes: 1 (CMT1B, HMSN1B), 17 (CMT1A), and X (CMTX). In this study multipoint linkage analysis of two Duffy-linked families given a combined LOD score of 8.65 to establish that the Duffy-linked CMT1B gene exists in the 18 centimorgan region between the antithrombin III gene and the Duffy/ sodium-potassium ATPase loci. The simultaneous segregation of polymorphisms near the CMT1A locus on chromosome 17 excludes linkage to this chromosome region in both families. Polymorphic sites that flank the CMT1B gene have been subchromosomally localized to the proximal chromosome-1 long arm (1q21.2?1q25) by spot blot analysis of sorted chromosomes, polymorphic deletion analysis, in situ hybridization, and multipoint linkage analysis.

The distribution of Q-band heteromorphisms in three Kuwaiti communities is reported. Of particular significance is the finding of large-Y segregating at a very high frequency (61.9%) in the Ajman tribesmen; and the absence of small-Y in the two tribal communities. The large variation in size of the Y-chromosome may reflect a unique cytogenetic feature of the inhabitants of the Arabian peninsula.

Frequency estimates were determined on seventeen blood group, serum protein, and red-cell enzyme markers on random samples of 193 individuals from two Bedouin tribes in addition to the general population in Kuwait. Genetic heterogeneity between the three communities is evident from the significant differences in allelic distribution of the polymorphic markers.

ABSTRACT: The low-density lipoprotein receptor-related protein gene (LRP1) is often mentioned as a candidate gene for Alzheimer disease (AD) because of its role as a receptor for apolipoprotein E (apoE), a major genetic risk factor for late-onset familial and sporadic AD. A recent association study of a tetranucleotide repeat polymorphism located 5′ to the LRP1 gene detected an increase in the 87 base pair allele in AD cases compared to unaffected controls. Additionally, an independent study involving a genomic screen for genes associated with late-onset AD identified a region as a possible location of a late-onset AD gene on chromosome 12p between D12S373 and D12S390, about 10 cM proximal to LRP1. We examined 144 late-onset multiplex AD families, 436 sporadic AD cases, and 240 controls and found no evidence of linkage or association of LRP1 and AD. Our data indicate that genetic variation of the LRP1 gene is not a major risk factor in the etiology of AD.

• Huntington's disease (HD) is an autosomal dominant disorder with variable age at onset and variable symptoms. Results from an analysis of questionnaire data on ages at onset and death, sex of the affected parent, and motor disorder in 624 patients gave no evidence of discrete phenotypes, as suggested in the literature. The tendency for muscular rigidity (instead of chorea), an accelerated natural history and paternal transmission, each of which is often associated with the juvenile-onset form of HD, is inversely related to age at onset in the affected child. The most parsimonious explanation for clinical variability in HD is that all HD types are part of a continuum, although expression of the juvenile form may be partly determined by a maternally transmitted factor. Evidence for accelerated aging in HD and correlations between age at onset and death in patients with HD and longevity in their unaffected relatives warrant further investigation into the relationship between aging and phenotypic expression of HD.

A total of 969 (73%) of 1,328 patients with cases of suspected transient ischemic attacks (TIAs) who came to six institutions during a 21-month period were followed up. Factors were identified and prospectively analyzed for risk for further TIAs, stroke, and death. A history of multiple carotid artery TIAs was significantly related to further TIAs. A single TIA placed the patient at greater risk for early infarction. Older age, male sex, and unreliability to take dangerous medication were risk factors for cerebral infarction. Anticoagulant therapy, older age, male sex, diabetes mellitus, heart disease, abnormal ECG, and poor surgical risk were factors for death. The increased mortality associated with anticoagulants was confined to the older age group. While white patients treated with antiplatelet-aggregating agents had a lower mortality than those treated otherwise, this was not true among black patients.(JAMA 240:742-746, 1978)

We have generated an 18-interval contiguous genetic linkage map of human chromosome 4 spanning the entire short arm and proximal long arm. Fifty-seven polymorphisms, representing 42 loci, were analyzed in the Venezuelan reference pedigree. The markers included seven genes (ADRA2C, ALB, GABRB1, GC, HOX7, IDUA, QDPR), one pseudogene (RAF1P1), and 34 anonymous DNA loci. Four loci were represented by microsatellite polymorphisms and one (GC) was expressed as a protein polymorphism. The remainder were genotyped based on restriction fragment length polymorphism. The sex-averaged map covered 123 cM. Significant differences in sex-specific rates of recombination were observed only in the pericentromeric and proximal long arm regions, but these contributed to different overall map lengths of 115 cM in males and 138 cM in females. This map provides 19 reference points along chromosome 4 that will be particularly useful in anchoring and seeding physical mapping studies and in aiding in disease studies.

Angiographic procedures were carried out on 36% of 1,328 patients suspected of having transient ischemic attacks (TIA). Among six participating centers, this ranged from 12% to 82%. This large difference might be related to the number of patients considered good surgical candidates and differences in the use of screening noninvasive diagnostic techniques. Arch studies, using catheter techniques, were performed most often. Although 13% of the patients had transient complications, permanent neurological deficits occurred in only 0.65%. Angiographic lesions were best correlated to clinical symptoms in those patients thought to definitely have carotid artery system TIA but were commonly seen in all other groups. Thus, clinical correlation was poor.(JAMA 237:2202-2206, 1977)

All patients (1,328) suspected of having transient ischemic attacks (TIA) who came to six institutions over a 21-month period were identified. Each case was reviewed by a neurological investigator, and a definite diagnosis of TIA was supported in 39% and ruled out in 30%. The reliability of the neurologist's review diagnosis was assessed by three methods, and close agreement (84% to 93%) was obtained. Factors demonstrated to effect the diagnosis were historical information, neurological training of the examiners, type of symptom complex, presence of carotid artery bruits, and examination during an attack.(JAMA 238:2029-2033, 1977)

All patients (1,328) suspected of having transient ischemic attacks (TIA) who came to six institutions during a 21-month period were identified. Symptoms and symptom complexes were related to the clinical diagnoses by cross-tabulation, factor analysis, and discriminant analysis. The diagnoses obtained by the discriminant analysis program were comparable to those of reviewing clinical neurologists. Symptoms of importance in the vertebral-basilar system (VBS) were bilateral visual blurring, diplopia, ataxia, and dizziness; in either carotid system (CAS), ipsilateral monocular visual disturbance and contralateral weakness or sensory complaints; in the left CAS, language disturbances; and in those whose ultimate diagnosis was not TIA, loss of consciousness, confusion, and bilateral leg weakness. Patients with VBS TIAs have symptoms common to conditions that are not TIA and have a greater variety of symptoms and more combinations of symptoms than CAS TIA.(JAMA 238:2386-2390, 1977)

Examination during an episode of transient ischemic attack (TIA) was performed on 121 of 1,307 patients suspected of having a single type of TIA. This examination supported the diagnosis of TIA in 79 patients and contributed to the establishment of a diagnosis other than TIA in 42. Although the examination increased diagnostic reliability, it did not always result in a definite diagnosis. The most common neurologic findings during a TIA were weakness of an arm or side of the face. Important findings not suggested by history included visual defects and blood pressure fluctuation. Also unexpected were the absence of findings such as sensory deficits in the presence of sensory complaints, retinal emboli, and cardiac abnormalities. Severe arteriosclerotic disease was less evident, the attacks were longer and more severe, and monocular blindness was rare.(JAMA 238:2512-2515, 1977)

Primary pulmonary hypertension (PPH)f an often fatal disease, is characterized by elevated pulmonary artery pressures in the absence of a secondary cause1. Endovascular occlusion in the smallest pulmonary arteries occurs by proliferation of cells and matrix, with thrombus and vasospasm2. Diagnosis is often delayed because the initial symptoms of fatigue and dyspnea on exertion are nonspecific and definitive diagnosis requires invasive procedures. The average life expectancy after diagnosis is two to three years with death usually due to progressive right heart failure3. The aetiology of the disease is unknown. Although most cases appear to be sporadic, ∼6% of cases recorded in the NIH Primary Pulmonary Hypertension Registry are inherited in an autosomal dominant manner with reduced penetrance4–6. Following a genome-wide search using a set of highly polymorphic short tandem repeat (STR) markers and 19 affected individuals from six families, initial evidence for linkage was obtained with two chromosome 2q markers. We subsequently genotyped patients and all available family members for 19 additional markers spanning ∼40 centiMorgans (cM) on the long arm of chromosome 2. We obtained a maximum two-point lod score of 6.97 at θ=0 with the marker D2S389; multipoint linkage analysis yielded a maximum lod score of 7.86 with the marker D2S311. Haplotype analysis established a minimum candidate interval of ∼25 cM.

P0, a major structural protein of peripheral myelin, is a homophilic adhesion molecule and maps to chromosome 1q22–q23, in the region of the locus for Charcot–Marie–Tooth neuropathy type 1B (CMT1B). We have investigated P0as a candidate gene in two pedigrees with CMT1B and found point mutations which are completely linked with the disease (\[zcirc]=5.5, Θ=0). The mutations, glutamate substitution for lysine 96 or aspartate 90, are located in the extracellular domain, which plays a significant role in myelin membrane adhesion. Individuals with CMT1B are heterozygous for the normal allele and the mutant allele. Our results indicate that P0is a gene responsible for CMT1B.

The Indiana kindred variant of Gerstmann-Sträussler-Scheinker disease has amyloid plaques that contain prion protein (PrP), but is atypical because neurofibrillary tangles like those of Alzheimer disease are present. To map the position of the disease causing gene, we used three markers for linkage analyses. A missense mutation at codon 198 of the PrP gene (PRNP) is found in all definitely affected individuals and yields a maximum lod score of 6.37 (Θ= 0). The disease also is concordant with the two other PRNP-region markers. These results demonstrate tight linkage of the disease-causing gene to PRNP and support the hypothesis that the codon 198 mutation is the cause of IK-GSS. Our studies also suggest that methionine/valine heterozygotes at PRNP codon 129 have a later age of onset of the disease than codon 129 valine/valine homozygotes.

A population association between a regulatory variation in the promoter of the serotonin transporter gene (HTT)and severe alcohol dependence was recently reported. We analyzed this potential association in a large number of systematically ascertained families in the United States; these families had at least three first‐degree relatives who were alcohol‐dependent. Analyses focused on individuals defined as alcohol‐dependent by criteria from ICD‐10 and on subsets of these individuals reporting withdrawal‐related symptoms. Application of the transmission disequilibrium test did not provide support for either linkage or association between this functional polymorphism and alcohol dependence; there was no significant bias in the transmission of either allele to the alcohol‐dependent offspring. We also report that African Americans differ from Caucasians in allele frequencies for this polymorphism.

Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3–8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50–60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. Multipoint methods provided the strongest suggestions of linkage with susceptibility loci for alcohol dependence on chromosomes 1 and 7, and more modest evidence for a locus on chromosome 2. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:207–215, 1998. © 1998 Wiley-Liss, Inc.

Careful comparison of symptomatic individuals with normal controls has revealed the primary biochemical abnormality in many human genetic diseases, particularly recessive disorders1. This strategy has proved less successful for most human disorders which are not recessive, and where a single copy of the aberrant gene has clinically significant effects even though the normal gene product is present. An alternative approach that eliminates the impediment of a normal protein in affected individuals is to study homozygotes for the mutant allele2. For virtually all dominant human disorders in which homozygotes have been described, symptoms have been significantly more severe in the homozygote than in the heterozygote3. Thus, these disorders do not conform to the classical definition of dominance which states that homozygotes and heterozygotes for a defect are phenotypically indistinguishable3–5. Instead, they display incomplete dominance, indicating that the normal allele may play a role in ameliorating the disease process. The D4S10locus, defined by the probe G8 and linked to the gene for Huntington's disease (HD), has permitted us to identify individuals with a high probability of being homozygous for this autosomal dominant neurodegenerative disorder6–9. These homozygotes do not differ in clinical expression or course from typical HD heterozygotes. HD appears to be the first human disease of genetically documented homozygosity that displays complete phenotypic dominance.

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.

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 (θ) 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. Am. J. Med. Genet. 74:238–246, 1997. © Wiley-Liss, Inc.

One would like to claim that the Hereditary Disease Foundation showed extraordinary prescience in choosing workshop topics in 1983. But perhaps it was more of the same good fortune that characterized the discovery of a DNA polymorphism closely linked to the gene for Huntington's disease (HD). Feeling confident that the search for a marker was well under way (the topic of previousSee also p 82.workshops during the past five years), the Foundation began to plan for the future, when a marker would be found. A basic research workshop held in May 1983, was entitled "What Can Be Learned About Huntington's Disease Once the Gene Has Been Located?" This workshop took place in Cambridge, Mass, and was chaired by one of us (D.H.) and Richard Mulligan, PhD. The May workshop ended with genuine offers of assistance some five or ten years hence, when a marker would be found, and sobriety for the distance to be traveled.

To better understand transient ischemic attacks (TIA), all patients (1,328) with TIA-like symptoms were identified at six participating institutions representing known variations in geography, referral patterns, and socioeconomic status. A total of 954 patients were observed for a mean of 14.3 months. Problems in diagnosis are defined, demographic information is summarized, and features of the history, examination, tests, and treatments are noted.(JAMA 237:882-886, 1977)

Variations in therapy for patients with complaints suggesting transient ischemic attacks (TIAs) among six participating medical centers are described. Selected treatment, based on clinical interpretation of patient characteristics, varied widely among centers. Therefore, results cannot be attributed to specific treatment. Nevertheless, there was little difference between treatment categories and the likelihood of further TIAs. The mortality of the patients who had received anticoagulants was significantly higher (P <.001) than those patients receiving other treatment. Possible reasons for these differences are discussed.(JAMA 238:142-146, 1977)

Family studies show that the Huntington's disease gene is linked to a polymorphic DNA marker that maps to human chromosome 4. The chromosomal localization of the Huntington's disease gene is the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder.

There is substantial evidence for a significant genetic component to the risk for alcoholism. In searching for genes that contribute to this risk, the diagnostic criteria for alcohol dependence may not be the optimal phenotype; rather, creation of a more homogeneous phenotype will lead to a more homogeneous genetic etiology. Items from the Semi‐Structured Assessment for the Genetics of Alcoholism collected from 830 individuals in 105 alcoholic families were used in a latent class analysis to identify a more homogeneous alcoholism‐related phenotype. A four‐class solution was chosen: class 1, unaffected group; class 2, mildly problematic group; class 3, moderately affected group; and class 4, severely affected group. Classes 3 and 4 had higher symptom endorsement probabilities than classes 1 and 2 for items reflecting severe alcohol dependence, and were combined to provide enough sibling pairs for genetic linkage analysis. A total of 291 markers distributed throughout the genome, with an average intermarker distance of 14 cM, were genotyped. Linkage analysis was performed to detect loci underlying classes 3 and 4, the moderately and severely affected alcoholics, of whom 88% met the Collaborative Study of the Genetics of Alcoholism, and >99% met ICD‐10 criteria for alcohol dependence. Evidence for a locus on chromosome 16, near the marker D16S675, was found with a maximum multipoint lod score of 4.0. Analysis of additional markers on chromosome 16 yielded a lod score of 3.2, narrowed the critical region, and placed the gene between D16S475 and D16S675 in a 15 cM interval.

The idea that alcoholism is familial has been accepted for centuries. However, familial does not translate directly to hereditary. Studies on twins, raised together and apart (adoption studies), clearly show that there is a major genetic component to alcoholism. In fact, more recent studies on a total of 1775 children born to single mothers in Stockholm, Sweden, between 1930 and 1949, their adoptive families, and their biological parents have identified at least two of the following classes of alcoholics: milieu-limited (type 1) and malelimited (type 2). Although type 2 alcoholism is more frequent in men, their female siblings show an abnormally high prevalence of somatization disorder. Type 2 alcoholism is highly inheritable from father to son, regardless of environmental background. On the other hand, in the Swedish adoption study, the risk of type 1 alcoholism to siblings increased as a function of both biological family history and adoptive environment.1

Information was collected among six participating medical centers on the frequency of performance and the percentage of abnormality of 30 tests performed on patients with complaints suggesting transient ischemic attacks (TIAs). A number of these were commonly performed and commonly exhibited abnormalities. Although the diagnosis of TIA is made by history and physical examination, these tests were of value in aiding the physician to determine possible causes of TIA, to detect risk factors of associated conditions, to rule out alternative diagnoses, and to assess the patient's ability to tolerate different types of therapy.(JAMA 239:2001-2003, 1978)

The idea that alcoholism is familial has been accepted for centuries. However, familial does not translate directly to hereditary. Studies on twins, raised together and apart (adoption studies), clearly show that there is a major genetic component to alcoholism. In fact, more recent studies on a total of 1775 children born to single mothers in Stockholm, Sweden, between 1930 and 1949, their adoptive families, and their biological parents have identified at least two of the following classes of alcoholics: milieu-limited (type 1) and malelimited (type 2). Although type 2 alcoholism is more frequent in men, their female siblings show an abnormally high prevalence of somatization disorder. Type 2 alcoholism is highly inheritable from father to son, regardless of environmental background. On the other hand, in the Swedish adoption study, the risk of type 1 alcoholism to siblings increased as a function of both biological family history and adoptive en-See

Bilateral acoustic neurofibromatosis (BANF) is a severe autosomal dominant disorder involving development of multiple tumours of the nervous system including meningiomas, gliomas, neurofibromas and particularly bilateral acoustic neuromas. We have used genetic linkage analysis with DNA markers to establish that the defective gene causing BANF is on chromosome 22, and is therefore distinct from the gene for the von Recklinghausen form of neurofibromatosis, which maps to chromosome 17. Linked DNA markers will be particularly valuable in BANF, facilitating early detection of tumours and thereby permitting more effective surgical intervention. In view of the reported loss of genes on chromosome 22 in meningiomas and acoustic neuromas, the genetic localization of the primary BANF defect strongly supports the concept that the disease locus encodes a 'tumour suppressor' gene. Isolation of this gene should provide insights into the pathogenesis of acoustic neuromas and other nervous system tumours, as well as into the control of proliferation and differentiation of neural crest cells.

Amyloid β-protein (AP) is a peptide of relative molecular mass (Mr) 42,000 found in the senile plaques, cerebrovascular amyloid deposits, and neurofibrillary tangles of patients with Alzheimer's disease and Down's syndrome (trisomy 21)1–4. Recen t molecular genetic evidence has indicated that AP is encoded as part of a larger protein by a gene on chromosome 21 (refs 5–7). The defect in the inherited autosomal dominant form of Alzheimer's disease, familial Alzheimer's disease (FAD), has been mapped to the same approximate region of chromosome 21 by genetic linkage to anonymous DNA markers8, raising the possibility that this gene product, which could be important in the pathogenesis of Alzheimer's disease, is also the site of the inherited defect in FAD (ref. 5). We have determined the pattern of segregation of the AP gene in FAD pedigrees using restriction fragment length polymorphisms. The detection of several recombination events with FAD suggests that the AP gene is not the site of the inherited defect underlying this disorder.