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Malaysiana 49(3)(2020): 635-642 http://dx.doi.org/10.17576/jsm-2020-4903-18 DNA Methylation Analysis of
AKT1 Promoter and HTR2A Exon-I of Malaysian Schizophrenia Multiplex Families with Lower Cognitive Performance (Analisis Metilasi DNA Promoter AKT1 dan Exon-I HTR2A pada Keluarga Skizofrenia
di Malaysia dengan Prestasi Kognitif Rendah) ERNA LAERE1,
TZE JEN CHOW2,
PEK YEE TANG2, SIEW YIM LOH3, HOI SEN YONG4,
ABDUL KADIR, ABU BAKAR5 & SHIAU FOON TEE1* 1Lee Kong Chian, Faculty
of Engineering and Science, Department of Chemical Engineering,
Universiti Tunku Abdul Rahman, Jalan Sungai Long, Bandar Sungai
Long, Cheras 43000 Kajang, Selangor Darul Ehsan, Malaysia 2Lee Kong Chian, Faculty
of Engineering and Science, Department of Mechatronics and Biomedical
Engineering, Universiti Tunku Abdul Rahman, Jalan Sungai Long, Bandar
Sungai Long, Cheras 43000 Kajang, Selangor Darul Ehsan, Malaysia 3Faculty of Medicine,
University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia 4Institute of Biological
Sciences, University of Malaya, 50603 Kuala Lumpur, Federal Territory,
Malaysia 5Jalan Persiaran Kempas
Baru, 81200 Johor Bahru, Johor Darul Takzim, Malaysia Received:
2 October 2018/Accepted: 6 March 2019 ABSTRACT
Dysfunction of cognitive performance
in schizophrenia has been associated with aberrant alteration of
DNA methylation of several schizophrenia-risk genes. AKT1 and
HTR2A are among the candidate genes for schizophrenia. Their
expressions were found reduced in schizophrenia patients. Thus,
we aimed to study the methylation status of AKT1 promoter
and HTR2A exon-I in Malaysian schizophrenia patients and
their affected family members. In this study, each participant was
required to perform Trail Making Test (TMT) part A and B to measure
their cognitive performance. Genomic DNA extracted from the peripheral
blood of 12 Malaysian schizophrenia families and 12 controls families,
was subjected to bisulfite conversion. The methylation status of
CpG sites of AKT1 promoter at Chr14: 104796054 and HTR2A
exon-I at Chr13: 46896918 were identified using methylation-specific
polymerase chain reaction (MSP). Our results showed that schizophrenia
patients performed worse in both TMT-A and B (p<0.0001) than
healthy controls. The patients also displayed significantly (p=0.023)
high level of methylation in AKT1 promoter
compared to controls. Meanwhile, no significant difference (p=0.248)
in methylation status was observed in HTR2A exon-I between
schizophrenia and control groups. Therefore, methylation of AKT1
promoter in peripheral bloods of patients may involve in cognitive
impairment and schizophrenia pathology. In addition, we were able
to demonstrate the heritability of DNA methylation status across
family members. Keywords: Cognitive performance;
DNA methylation; schizophrenia; Trail-Making Test Abstrak Disfungsi prestasi kognitif
dalam skizofrenia telah dikaitkan dengan perubahan metilasi DNA
pada beberapa gen yang berisiko menyebabkan
skizofrenia. AKT1 dan HTR2A adalah antara calon
gen
kepada skizofrenia. Ekspresi gen-gen tersebut didapati berkurangan pada pesakit skizofrenia.
Oleh itu, kertas ini bertujuan untuk mengkaji status
metilasi promoter AKT1 dan exon-I HTR2A pada pesakit skizofrenia
di Malaysia dan juga ahli keluarga mereka yang menghidap skizofrenia.
Dalam kajian ini, setiap peserta dikehendaki melakukan Ujian Membuat
Jejak (TMT) bahagian A dan B untuk mengukur prestasi kognitif mereka.
DNA genom yang telah diekstrak daripada darah periferal 12 keluarga
skizofrenia di Malaysia dan 12 keluarga kawalan sihat, tertakluk
kepada penukaran bisulfite. Status metilasi tapak CpG dalam promoter
AKT1 di Chr14: 104796054 dan dalam exon-I HTR2A
di Chr13: 46896918 dikaji dengan menggunakan metilasi-khusus
tindak balas rantaian polimerase (MSP). Keputusan
menunjukkan bahawa pesakit skizofrenia mendapat
keputusan yang teruk dalam kedua-dua bahagian
TMT-A dan
B (p<0.0001) berbanding dengan kawalan sihat. Pesakit skizofrenia
juga menunjukkan
tahap metilasi promoter AKT1 yang tinggi secara signifikan
berbanding dengan kawalan (p=0.023). Sementara itu, tiada perbezaan
yang signifikan (p=0.248) diperhatikan dalam metilasi status exon-I
HTR2A antara
kumpulan skizofrenia dan kawalan sihat. Kertas
ini menunjukkan bahawa metilasi promoter AKT1 dalam
darah periferal pesakit skizofrenia mungkin terlibat dalam kecacatan
kognitif dan patologi skizofrenia. Tambahan pula, kami dapat menunjukkan
bahawa kewarisan status metilasi DNA dalam kalangan
ahli keluarga. Kata kunci: Metilasi
DNA; prestasi kognitif; skizofrenia; Ujian
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*Corresponding author;
email: teesf@utar.edu.my
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