TY - JOUR
T1 - Convergent patterns of association between phenylalanine hydroxylase variants and schizophrenia in four independent samples
AU - Talkowski, Michael E.
AU - McClain, Lora
AU - Allen, Trina
AU - Bradford, L. Di Anne
AU - Calkins, Monica
AU - Edwards, Neil
AU - Georgieva, Lyudmila
AU - Go, Rodney
AU - Gur, Ruben
AU - Gur, Raquel
AU - Kirov, George
AU - Chowdari, Kodavali
AU - Kwentus, Joseph
AU - Lyons, Paul
AU - Mansour, Hader
AU - McEvoy, Joseph
AU - O'Donovan, Michael C.
AU - O'Jile, Judith
AU - Owen, Michael J.
AU - Santos, Alberto
AU - Savage, Robert
AU - Toncheva, Draga
AU - Vockley, Gerard
AU - Wood, Joel
AU - Devlin, Bernie
AU - Nimgaonkar, Vishwajit L.
PY - 2009/6/5
Y1 - 2009/6/5
N2 - 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: χ2 = 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.
AB - 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: χ2 = 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.
KW - Phenylalanine hydroxylase
KW - Polymorphism
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=66649099684&partnerID=8YFLogxK
U2 - 10.1002/ajmg.b.30862
DO - 10.1002/ajmg.b.30862
M3 - Article
C2 - 18937293
AN - SCOPUS:66649099684
SN - 1552-4841
VL - 150
SP - 560
EP - 569
JO - American Journal of Medical Genetics - Neuropsychiatric Genetics
JF - American Journal of Medical Genetics - Neuropsychiatric Genetics
IS - 4
ER -