Y chromosome haplogroups and prostate cancer in populations of European and Ashkenazi Jewish ancestry

Abstract

Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I (P = 0.012, OR = 0.51; 95% confidence interval 0.30-0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry (P(meta) = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk (P(meta) = 0.010, OR = 0.77; 95% confidence interval 0.62-0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds.

Fig. 1

Chromosome Y haplogroup tree and frequency distribution in control subjects of European ancestry in Stage I. a Chromosome Y tree showing genotyped markers in black and those not genotyped in light grey. Haplogroup names are according to the International Society of Genetic Genealogy (ISOGG) 2011 update. The arrow points to the mutational event which gave rise to the E1b1b1c haplogroup. Stage I studies are the following: CPS-II American Cancer Society Cancer Prevention Study II, ATBC Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, CeRePP Centre de Recherche pour les Pathologies Prostatiques, and PLCO Prostate, Lung Colorectal and Ovarian Cancer Screening Trial. b The circle plots show frequencies for haplogroups with a derived frequency of 5% or higher in different colors for each Stage I cohort (remaining haplogroups are combined in one group shown in black)

Fig. 2

Population substructure analysis by principal component analysis and comparison to CGEMS prostate cancer GWAS. a shows the distribution of the first two principal components, EV1 and EV2, for carriers of E1b1b1c (filled squares) and R1b1a2 (open circles) haplogroups in Stage I. Circles and squares denote eigenvalues from PCA analysis for each individual. The distribution of EV1 and EV2 for all Stage I subjects is shown in b. Studies are designed by different colors. CPS-II Blood blood derived DNA samples were used for genotyping, CPS-II Buccal buccal derived DNA samples were used for genotyping. DNA samples from ATBC, CeRePP and PLCO were all derived from blood. Individuals of inferred Ashkenazi Jewish ancestry are circled. PCA results were performed by EIGENSTRAT in CGEMS prostate cancer GWAS (Thomas et al. ; Yeager et al. 2007, 2009)