Convergent patterns of association between phenylalanine hydroxylase variants and schizophrenia in four independent samples.

Abstract

Recessive mutations in the phenylalanine hydroxylase (PAH) gene predispose to phenylketonuria (PKU) in conjunction with dietary exposure to phenylalanine. Previous studies have suggested PAH variations could confer risk for schizophrenia, but comprehensive follow-up has not been reported. We analyzed 15 common PAH "tag" SNPs and three exonic variations that are rare in Caucasians but common in African-Americans among four independent samples (total n = 5,414). The samples included two US Caucasian cohorts (260 trios, 230 independent cases, 474 controls), Bulgarian families (659 trios), and an African-American sample (464 families, 401 controls). Analyses of both US Caucasian samples revealed associations with five SNPs; most notably the common allele (G) of rs1522305 from case-control analyses (z = 2.99, P = 0.006). This SNP was independently replicated in the Bulgarian cohort (z = 2.39, P = 0.015). A non-significant trend was also observed among African-American families (z = 1.39, P = 0.165), and combined analyses of all four samples were significant (rs1522305: chi(2) = 23.28, 8 d.f., P = 0.003). Results for rs1522305 met our a priori criteria for statistical significance, namely an association that was robust to multiple testing correction in one sample, a replicated risk allele in multiple samples, and combined analyses that were nominally significant. Case-control results in African-Americans detected an association with L321L (P = 0.047, OR = 1.46). Our analyses suggest several associations at PAH, with consistent evidence for rs1522305. Further analyses, including additional variations and environmental influences such as phenylalanine exposure are warranted.

• Authors: Michael E Talkowski, Lora McClain, Trina Allen, L Dianne Bradford, Monica Calkins, Neil Edwards, Lyudmila Georgieva, Rodney Go, Ruben Gur, Raquel Gur, George Kirov, Kodavali Chowdari, Joseph Kwentus, Paul Lyons, Hader Mansour, Joseph McEvoy, Michael C O'Donovan, Judith O'Jile, Michael J Owen, Alberto Santos, Robert Savage, Draga Toncheva, Gerard Vockley, Joel Wood, Bernie Devlin, Vishwajit L Nimgaonkar
• Journal: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics (Am J Med Genet B Neuropsychiatr Genet) Vol. 150B Issue 4 Pg. 560-9 (Jun 05 2009) ISSN: 1552-485X [Electronic] United States
• PMID: 18937293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Phenylalanine Hydroxylase

Topics

• Alleles
• Case-Control Studies
• Female
• Gene Frequency (genetics)
• Genetic Predisposition to Disease
• Genotype
• Humans
• Linkage Disequilibrium (genetics)
• Male
• Mutation (genetics)
• Phenylalanine Hydroxylase (genetics)
• Phenylketonurias (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Schizophrenia (genetics)