ASHG 2010 abstracts on Jewish genetics

Selected abstracts from the 2010 meeting of the American Society of Human Genetics.

ABRAHAM’S CHILDREN IN THE GENOME ERA 2: A WORLDWIDE VIEW OF JEWISH DIASPORA GROUPS. G. Atzmon1,2, L. Hao3, I. Pe'er4, C. Velez5, A. Pearlman5, P. F. Palamara5, E. Friedman6, C. Oddoux5, E. Burns1, H. Ostrer5 1) Department of Medicine, Albert Einstein College of Medicine, Bronx, NY; 2) Department of Genetics, Albert Einstein College of Medicine, Bronx, NY; 3) Center for Genome Informatics, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ; 4) Department of Computer Science, Columbia University, New York, NY; 5) Human Genetics Program, Department of Pediatrics, New York University School of Medicine, New York, NY; 6) The Susanne Levy Gertner Oncogenetics Unit, the Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621, Tel-Hashomer, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv Israel.

Genome wide analysis of Jewish Diaspora groups that have formed over the past 2000 years provides an invaluable opportunity for understanding genetic origins and migrations and provides a framework for elucidating the genetic basis of complex disorders. Here, we have built upon our initial genome wide analysis of 7 ethnically diverse, healthy Jewish (European: Ashkenazi, Italian, Greek, Turkish, and Middle Eastern: Iranian, Iraqi, and Syrian) populations (AJHG online June 3rd, 2010) by analyzing members of an additional 9 Jewish communities (North African: Moroccan, Algerian, Tunisian, Djerban, and Libyan; and Georgian, Yemenite, Indian Bene Israel and Ethiopian). These 524 unrelated individuals were analyzed on Affymetrix v6 microarrays, then merged with results from the Human Genome Diversity Project and the Population Reference Sample studies that were comprised of 146 non-Jewish Middle Easterners (Druze, Bedouin and Palestinian), 30 northern Africans (Mozabite from Algeria), 1547 Europeans, and 653 individuals from other African, Asian, Latin American, and Oceanian populations. Principal component SNP and CNV analysis (PCA) and pairwise Fst distance showed that European, Middle Eastern, North African and Georgian Jewish populations formed a cluster clearly distinct from all major continental populations with each group demonstrating significant admixture with local populations. Yemenite, Ethiopian and Indian (Bene Israel) Jews fell outside this cluster. The North African Jewish cluster demonstrated proximity to the Sephardic Jewish. North African Jewish relationships showed a cline consistent with their geographic cline and the Tunisian Jewish population was statified into two subpopulations, one with proximity to Libyan and Djerban Jews and the other to Moroccan and Algerian Jews. Analysis of identity by descent revealed a high degree of segment sharing across most Jewish groups and endogamy within all of the Jewish populations that was especially high among the Indian and Djerban Jews. These results demonstrate the shared and distinctive genetic heritage of Jewish Diaspora groups that were formed during Classical Antiquity and indicate that both the flow of genes and the flow ideas has contributed to Jewishness.

Admixture in Ashkenazi Jewish cohorts and implications for association studies. V. Vacic1, E. E. Kenny1,2, A. Gusev1, I. Peter3, J. Cho4, G. Atzmon5, H. Ostrer6, S. B. Bressman5, I. Ozelius3, I. Pe'er1 1) Columbia University, New York, NY; 2) The Rockefeller University, New York, NY; 3) Mount Sinai School of Medicine, New York, NY; 4) Yale University, New Haven, CT; 5) Albert Einstein College of Medcine, Yeshiva University, New York, NY; 6) Langone Medical Center, New York University, New York, NY.

Studies of complex genetic disorders may benefit from focusing on population isolates, such as Ashkenazi Jews (AJ). However, in order to truly exploit the advantages of reduced genetic diversity the self-declared AJ ancestry of study participants should be independently confirmed with available genetic data. We investigate whether the AJ cohorts display genetic heterogeneity, such as e.g. different rate of admixing in cases and controls, which could potentially confound disease association studies. We applied principal component analysis (PCA) to AJ cohorts ascertained in Israel and the US East Coast with the goal of characterizing population structure. As described previously, when compared to the HapMap samples with CEU, YRI and CHB/JPT ancestry, virtually all AJ samples cluster with the CEU. Similar analysis done on CEU and Jewish HapMap samples from Ashkenazi, Sephardic and Middle Eastern Jewish communities revealed that 97.8% of AJ samples cluster along the AJ-CEU axis, with modes at AJ and CEU cluster centers and at approximately quartile distances between them. We postulate that these groups correspond to 100-0, 75-25, 50-50, 25-75, and 0-100% AJ-CEU admixtures. Notably, only 91.7% of self-reported AJ individuals fall into the reference JHapMap panel AJ cluster, with 1.6, 3.3, 0.5 and 0.7% in the admixed modes ordered by decreasing fraction of AJ ancestry. We also observe admixing with the non-AJ Jewish communities: 0.7% of samples fall within the non-AJ clusters and 1.4% at a subgroup approximately halfway between the AJ and non-AJ cluster centers. In our dataset we found that when compared to the sample as a whole or only to controls, individuals with Crohn’s disease (CD) show significantly more admixing: 78.1, 3.1, 8.5, 2.0 and 0.9% in the 100, 75, 50, 25 and 0% AJ subgroups respectively. Also, CD samples show more admixing with non-AJ groups (2.8 and 1.0% in the 50-50 and 0-100 AJ-non-AJ subgroups). Isolates typically exhibit a greater amount of cryptic relatedness compared to outbred populations, which motivates an orthogonal method for verifying AJ ancestry based on identity-by-descent (IBD). The high background level of IBD within the Ashkenazi Jewish community can be used to estimate degree of AJ ancestry by averaging the IBD between a sample under study and the AJ individuals in the JHapMap panel. Our preliminary results show that this method recapitulates the high-level results from the PCA analysis and provides better resolution.

Signatures of founder effects, admixture and selection in the Ashkenazi Jewish population. S. Bray1, J. Mulle1, A. Dodd1, A. Pulver2, S. Wooding3, S. Warren1 1) Department of Human Genetics, Emory University School of Medicine, Atlanta, GA; 2) Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD; 3) The McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas.

The Ashkenazi Jewish (AJ) population has long been viewed as a genetic isolate, yet despite decades of population genetic studies, we still lack definitive evidence of founder events or positive selection. Here we analyzed a large AJ cohort and found higher linkage disequilibrium (LD) and identity-by-descent, as expected for an isolate. However, paradoxically we also found higher genetic diversity relative to Europeans, a sign of an older or more admixed population but not of a long-term isolate. Further analysis indeed revealed higher than expected levels of admixture with Europeans, likely accounting for the increased genetic variation. Moreover, we demonstrate that admixture also correlates with high LD, suggesting that the AJ population has undergone gradual admixture with neighboring populations, increasing both its genetic diversity and LD, yet still maintaining some shared haplotypes from founding events. Additionally, we applied extended haplotype tests to determine whether positive selection can account for the level of AJ-prevelant diseases. We identified genomic regions under selection that account for lactose and alcohol tolerance in the AJ population, and while we found evidence for positive selection of some loci responsible for AJ-prevalent genetic diseases, the higher incidence of the majority of these loci is likely the result of genetic drift. Thus, the AJ population shows some evidence of past founding events, however, admixture and selection have also strongly influenced its current genetic structure.

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