PLoS Genet. 2012;8(4):e1002656. doi: 10.1371/journal.pgen.1002656. Epub 2012 Apr 12.
Runs of homozygosity implicate autozygosity as a schizophrenia risk factor.
St Clair D, Cichon S, Rietschel M, Nöthen MM, Maier W, Schulze TG, Mattheisen M, Kirov GK, O'Donovan MC, Holmans PA, Georgieva L, Nikolov I, Williams HJ, Toncheva D, Milanova V, Owen MJ, O'Donovan MC, Craddock N, Holmans PA, Hamshere M, Williams HJ, Moskvina V, Dwyer S, Georgieva L, Zammit S, Owen MJ, Kirov GK, Sullivan PF, Lin DY, van den Oord E, Kim Y, Stroup T, Lieberman JA, Hansen T, Ingason A, Olsen L, Schmock H, Skjødt C, Thygesen JH, Rosengren A, Werge T, Morris DW, O'Dushlaine CT, Kenny E, Quinn EM, Gill M, Corvin A, Blackwood DH, McGhee KA, Pickard B, Malloy P, Maclean AW, McIntosh A, Gejman PV, Sanders AR, Duan J, Levinson DF, Shi J, Buccola NG, Mowry BJ, Freedman R, Amin F, Black DW, Silverman JM, Byerley WF, Cloninger C, Giegling I, Hartmann AM, Konnerth H, Friedl M, Konte B, Muglia P, Rujescu D, Pato MT, Pato CN, Fanous A, Hultman CM, Lichtenstein P, Bergen SE, Purcell S, Scolnick E, Sklar P, Sullivan PF, Djurovic S, Mattingsdal M, Agartz I, Melle I, Andreassen OA, Ophoff RA, Cantor RM, Freimer NB, Kahn RS, Linszen DH, van Os J, Wiersma D, Bruggeman R, Cahn W, de Haan L, Krabbendam L, Myin-Germeys I, Strengman E, McQuillin A, Choudhury K, Datta S, Pimm J, Thirumalai S, Puri V, Krasucki R, Lawrence J, Quested D, Bass N, Gurling H, Malhotra AK, Lencz T.
Source
Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, Colorado, United States of America. matthew.c.keller@gmail.com
Abstract
Autozygosity occurs when two chromosomal segments that are identical from a common ancestor are inherited from each parent. This occurs at high rates in the offspring of mates who are closely related (inbreeding), but also occurs at lower levels among the offspring of distantly related mates. Here, we use runs of homozygosity in genome-wide SNP data to estimate the proportion of the autosome that exists in autozygous tracts in 9,388 cases with schizophrenia and 12,456 controls. We estimate that the odds of schizophrenia increase by ~17% for every 1% increase in genome-wide autozygosity. This association is not due to one or a few regions, but results from many autozygous segments spread throughout the genome, and is consistent with a role for multiple recessive or partially recessive alleles in the etiology of schizophrenia. Such a bias towards recessivity suggests that alleles that increase the risk of schizophrenia have been selected against over evolutionary time.
- PMID:
- 22511889
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3325203
Free PMC ArticleFigure 1Distributions of ROH Lengths (left) and Froh (right) in the total sample.
Distributions are based on ROHs from the imputed SNP data. For clarity, the distribution of Froh leaves omits 15 individuals who have Froh>.0625.
PLoS Genet. 2012 April;8(4):e1002656.
Figure 2Estimated changes in odds of schizophrenia for each 1% increase in Froh (odds ratios; asterisks) and their 95% confidence intervals (bars) across the 17 datasets (colored) and for the total sample (black) from the imputed SNP data.
Boxes are proportional to the square root of sample sizes (also shown at the bottom). Dataset names are on the x-axis. Although none of the estimated odds ratios are significantly different from one individually, the overall effect (black) is highly significant.
PLoS Genet. 2012 April;8(4):e1002656.
Figure 3Slope estimates (the change in log odds for a 1% increase in Froh; points) and their 95% confidence intervals (bars) of Froh from imputed SNP data predicting schizophrenia for different SNP homozygosity thresholds of calling ROHs.
Minimum SNP thresholds for full and reduced models are offset for clarity. All ROH thresholds were significant; the most significant result was for ROHs defined as being 65 or more homozygous SNPs in a row.
PLoS Genet. 2012 April;8(4):e1002656.
Figure 4Distribution of ROH lengths for the 15 individuals with Froh>.0625 in the sample (blue) and the expected lengths of autozygous segments for different levels of inbreeding (red and orange).
Nearby ROHs that were broken up by a possible heterozygous SNP miscall were joined together. Assuming Haldane's recombination model, the length of an autozygous segment should follow an exponential distribution with mean equal to 1/(2×number of generations since the common ancestor) in Morgans. The figure shows that the distribution of ROH lengths among individuals with Froh>.0625 is most consistent with autozygosity caused by common ancestors between parents who lived ∼6 generations ago.
PLoS Genet. 2012 April;8(4):e1002656.
Figure 5Risk and protective effects of ROHs on schizophrenia risk and frequencies of ROHs across the autosome.
Top panel: −log10 p-values for the risk (red) and protective (blue) effects of ROHs on schizophrenia risk at each 500 kb region along the autosome. Bottom panel: frequencies of ROHs across the autosome.
PLoS Genet. 2012 April;8(4):e1002656.
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