Limited data suggest that atopic dermatitis (AD) may be more common among African Americans but whether differences are due to genetic factors, or differences in risk factors, environmental exposures, or treatment is unclear. Using two large US longitudinal cohorts, we aimed to determine whether AD is more common and more active among African Americans than whites, and whether this association varies by degree of African genetic ancestry. We analyzed data on AD prevalence from 88,893 individuals ages 18-100 in the Kaiser Permanente Northern California Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, and data on AD activity from 5,775 individuals ages 2-26 from the national Pediatric AD Elective Registry (PEER). For each participant, we estimated the proportion of African ancestry defined as the probability of a set of genotypes in an individual expressed as a weighted average of allele frequencies of putative ancestors, using ancestry informative markers (PEER) or genome-wide data (GERA). We then tested whether genetic ancestry was associated with the presence of AD or AD activity, respectively. AD was both more common among African Americans as compared to whites (12% vs 8%, OR 1.51, 95% CI 1.36-1.68 in multivariate models, GERA) and more active (94% vs 83% of follow-up time with active disease, OR 5.71, 95%CI 4.53-7.20 in multivariate models, PEER). African ancestry, however, did not have a statistically significant association with AD (GERA) or AD activity (PEER). Genetic factors are unlikely to explain the increased prevalence and disease activity among African Americans in two large US cohorts.

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans. We examined two statistically independent phenotypes reflecting subjects’ alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status) and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (odd ratio (OR)=0.40, P =2.28 × 10 −72 ) in East Asians, and also an effect on drinks/week (beta=−0.17, P =5.42 × 10 −4 ) in the same group. We also observed a genome-wide significant association in non-Hispanic whites between the previously reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, P =2.47 × 10 −20 for drinker status and beta=−0.19, P =1.91 × 10 −35 for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P =4.35 × 10 −7 and beta=−0.21, P =2.58 × 10 −6 , respectively). Although prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=−0.04, P =3.41 × 10 −10 for drinks/week and OR=0.96, P =4.08 × 10 −5 for drinker status), and rs4665985 (beta=0.04, P =2.26 × 10 −8 for drinks/week and OR=1.04, P =5 × 10 −4 for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2 , SGOL1 and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites.

The first‐line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome‐wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente's Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol‐related SUA reduction, first in the largest ethnic group, non‐Hispanic white (NHW) subjects, and then in a stratified transethnic meta‐analysis. ABCG2 , encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects ( P = 2 × 10 −8 ), and a missense allele (rs2231142) was associated with a reduced response ( P = 3 × 10 −7 ) in the meta‐analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug.

Eric Jorgenson1, Stan Sciortino1, Ling Shen1, Dilrini Ranatunga1, Thomas Hoffmann2, Mark Kvale2, Yambazi Banda2, Pui-Yan Kwok2, Lawrence Walter1, Neil Risch2 and Cathy Schaefer1 1Kaiser Permanente Northern California 2University of California, San Francisco

Ling Shen1, Thomas Hoffmann2, Mark Kvale2, Lori Sakoda1, Yambazi Banda2, Pui-Yan Kwok2, Neil Risch2, Eric Jorgenson1 and Cathy Schaefer1 1Kaiser Permanente Northern California 2University of California, San Francisco

Background: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. Mutations in 5 genes that raise susceptibility to GEFS+ have been discovered, but they account for only a small proportion of families. Methods: We identified a 4-generation family containing 15 affected individuals with a range of phenotypes in the GEFS+ spectrum, including febrile seizures, febrile seizures plus, epilepsy, and severe epilepsy with developmental delay. We performed a genome-wide linkage analysis using microsatellite markers and then saturated the potential linkage region identified by this screen with more markers. We evaluated the evidence for linkage using both model-based and model-free (posterior probability of linkage [PPL]) analyses. We sequenced 16 candidate genes and screened for copy number abnormalities in the minimal genetic region. Results: All 15 affected subjects and 1 obligate carrier shared a haplotype of markers at chromosome 6q16.3-22.31, an 18.1-megabase region flanked by markers D6S962 and D6S287. The maximum multipoint lod score in this region was 4.68. PPL analysis indicated an 89% probability of linkage. Sequencing of 16 candidate genes did not reveal a causative mutation. No deletions or duplications were identified. Conclusions: We report a novel susceptibility locus for genetic epilepsy with febrile seizures plus at 6q16.3-22.31, in which there are no known genes associated with ion channels or neurotransmitter receptors. The identification of the responsible gene in this region is likely to lead to the discovery of novel mechanisms of febrile seizures and epilepsy.

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through joint sponsorship of The Movement Disorder Society and The Parkinson Study Group. The Movement Disorder Society is accredited by the ACCME to provide continuing medical education for physicians. The symposium will consist of peer‐reviewed platform and poster presentations designed to communicate recent research advances in the field of Parkinson's disease, Huntington's disease, ataxia, dystonia, myoclonus, Tourette's syndrome, tremor and other Movement Disorders to professionals in neurology and related disciplines. Practitioners, educators, and researchers are invited to attend. Abstracts of platform and poster presentations representing original material will be published in the August 2008 issue of Movement Disorders. At the conclusion of this session, participants should be able to: 1) Identify by scholarly review, oral presentation and group discussion the current research into the diagnosis, prevention and treatment of Parkinson's disease and other Movement Disorders; 2) Identify the important advances in research and clinical treatments relating to a variety of Movement Disorders; 3) Discuss new pharmacological and non‐pharmacological treatment options available for Parkinson's disease and other Movement Disorders; 4) Identify the mechanisms (genetic, environmental, pathophysiology, neurobiology) linked to Parkinson's disease and other Movement Disorders; and 5) Discuss the diagnostic approaches and tools available for Parkinson's disease and other Movement Disorders.

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BACKGROUND:Multiple sclerosis (MS) is a disease that is widely believed to be autoimmune in nature. Genetic-epidemiological studies implicate susceptibility genes in the pathogenesis of MS, although non-MHC susceptibility linkages have been difficult to confirm. Insight into pathways that are intrinsic to other complex diseases has come from the genetic analysis of large, autosomal-dominant kindreds. Here, we present a genetic study of a large and unique kindred in which MS appears to follow an autosomal-dominant pattern of inheritance, with consistent penetrance in four generations. METHODS:Eighty-two individuals of this 370-member family were genotyped with 681 microsatellite markers spanning the genome, with an average spacing of 5.3 cM. RESULTS:Parametric linkage analysis was performed and no significant LOD score (LOD >3.3) was observed. For a rare dominant disease model with reduced penetrance, 99.6% of the genome was excluded at a LOD score <-1 and 96% at a LOD score <-2. The HLA-DRB1 candidate gene was also genotyped by allele-specific methods. In each instance where at least one parent was positive for HLA-DRB1*15, one or more HLA-DRB1*15 alleles were transmitted to the affected offspring (11/11). HLA-DRB1*15 was transmitted equally from both the familial and the married-in parents and therefore this locus does not appear to be an autosomal-dominant acting gene in this family but an important modifier of risk. CONCLUSIONS:These results further stress the importance of the HLA-DRB1*15-bearing haplotype in determining MS susceptibility. Furthermore, this study highlights the complexity of MS genetics, even in the presence of a single family, seemingly segregating MS as an autosomal-dominant trait.

Background: The two existing estimates of the incidence of primary cervical dystonia were based on observations in relatively ethnically homogeneous populations of European descent. Objective: To estimate the minimum incidence of primary cervical dystonia in the multiethnic membership of a health maintenance organization in Northern California. Methods: Using a combination of electronic medical records followed by medical chart reviews, we identified incident cases of cervical dystonia first diagnosed between 1997 and 1999. Results: We identified 66 incident cases of cervical dystonia from 8.2 million person-years of observation. The minimum estimate of the incidence of cervical dystonia in this population is 0.80 per 100,000 person-years. Ethnicity-specific incidence rates were calculated for individuals over age 30. Incidence was higher in white individuals (1.23 per 100,000 person-years) than in persons of other races (0.15 per 100,000 person-years, p < 0.0001). The minimum estimated incidence was 2.5 times higher in women than in men (1.14 vs 0.45 per 100,000 person-years, p = 0.0005). The average age at diagnosis was higher in women (56 years) than in men (45 years, p = 0.0004). There was no significant difference in reported symptom duration prior to diagnosis between women and men (3.9 vs 5.3 years). Conclusion: The estimated incidence of diagnosed cervical dystonia among white individuals in this Northern Californian population is similar to previous estimates in more ethnically homogeneous populations of largely European descent. The incidence in other races, including Hispanic, Asian, and black appears to be significantly lower. The incidence is also higher in women than in men.