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Genetic liability to schizophrenia in Oceanic Palau: a search in the affected and maternal generation

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Abstract

While liability to schizophrenia (Scz) is due to genetic and environmental factors, specific factors are largely unknown. We postulate a two-hit model for Scz, in which initial liability is generated during fetal brain development: this “hit” is precipitated by environmental stressors biologically interacting with maternal genetic vulnerability to the stress. Additional liability to Scz is generated by individual genetic vulnerability. To evaluate these putative levels of vulnerability, we search in the genome of both affected individuals and their mothers for variation that differs, statistically, from that in the general population. For parental analyses, mothers were treated as “affected,” rather than their offspring, and the fathers were treated as “controls”. We used a sample from the Palauan population: 175 individuals diagnosed with Scz, broadly defined; 87 mothers and 45 fathers of affected individuals. Pedigree and diagnostic data were available on 2,953 living and deceased subjects. DNA from 553 individuals was genotyped for short tandem repeats (STR) spaced approximately every 10 cM across the genome. We tested for association between affection status and STR alleles; such an approach was reasonable, despite the widely spaced markers, because this population has far-ranging linkage disequilibrium (LD). Results for the truly affected individuals were modest, whereas results from the maternal generation were promising. For a recessive model and a test for excess allele matching across mothers, significant findings occurred for D20S481, D10S1221, D6S1021, D13S317, and D18S976. Regions in which at least two adjacent markers produced substantial association statistics include 2p12-11.2, 2q24.1-32.1, 6q12-14.1, 10q23.2-24.21, 12q23.2-24.21 and 17q23.2-23.3.

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Acknowledgments

We thank the people of Palau for their participation in this study. We would like to acknowledge the insight of Robert Ferrell, who chose MBL2 as a gene of interest long before the results were in; we hope his insight continues to hold. We thank Vishwajit Nimgaonkar for many valuable discussions and for his comments on the manuscript. This research was supported by NIH grants MH057881, MH063295, and MH063356. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number N01-HG-65403. We thank CIDR for their excellent work.

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Correspondence to Bernie Devlin or Kathryn Roeder.

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Devlin, B., Klei, L., Myles-Worsley, M. et al. Genetic liability to schizophrenia in Oceanic Palau: a search in the affected and maternal generation. Hum Genet 121, 675–684 (2007). https://doi.org/10.1007/s00439-007-0358-7

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