Ika Yuni Widyawati

A family-based association study of DNA sequence variants in GRM7 with schizophrenia in an Indonesian population

We previously reported genome-wide significant linkage to chromosome 3p in a sib-pair family sample from Indonesia. A promising candidate gene within the linked region is the metabotropic glutamate receptor subtype 7 (GRM7), involved in glutamatergic neurotransmission. We genotyped 18 single nucleotide polymorphisms in GRM7 in the sample of 124 Indonesian sib-pair families that had provided the significant linkage finding. Transmission disequilibrium analysis revealed nominally significant transmission distortion of rs17031835 in intron 1 of GRM7 (p=0.004, before correction for multiple testing), along with haplotypes containing rs17031835. No other single marker was found to be significantly associated with schizophrenia in our sample. The results from our study provide support for the idea that glutamatergic neurotransmission and specifically the GRM7 gene might be relevant to the development of schizophrenia. Further studies supporting this finding are warranted.

Genome-wide scan in 124 Indonesian sib-pair families with schizophrenia reveals genome-wide significant linkage to a locus on chromosome 3p26-21†

Variation in incidence of schizophrenia between populations with different ethnical background may reflect population specific differences in nature and composition of genetic and environmental factors. In order to investigate whether there are population specific susceptibility genes for schizophrenia, we collected in Indonesia families with two or more affected siblings and, as far as available, parents and unaffected siblings, suitable for genetic linkage‐ and association studies. After checking extensively for incompatibilities with Mendelian inheritance as well as for errors in sampling, we used 124 families from the sample of 152 originally ascertained families for linkage analysis. Genotyping was performed at the NHLBI Mammalian Genotyping Service at Marshfield Research Organisation using the Screening Set 16, which comprises 402 Short Tandem Repeat Polymorphisms (STRPs). The genotypes of 540 individuals including 267 affected with schizophrenia were used for analysis. Multipoint sib‐pair linkage analysis was carried out by estimation of—allele sharing derived—maximum likelihood LOD scores (MLS) in 154 sib‐pair combinations. We obtained a genome‐wide significant MLS of 3.76 on chromosome 3p26.2‐25.3. Genome‐wide significance was estimated by performing 10,000 simulated genomescans. Additional loci were detected on 1p12, which produced suggestive evidence for linkage (MLS = 2.35), as well as on 5q14.1 (MLS = 1.56), 5q33.3 (MLS = 1.11), and 10q (MLS = 1.17), where linkage had been reported previously. In conclusion, our study detected a region with genome‐wide significant linkage, which will serve as starting point for identification of schizophrenia susceptibility genes in the Indonesian population.

Association of PIP5K2A with schizophrenia: a study in an Indonesian family sample

PIP5K2A variants have been shown to be associated with schizophrenia in Caucasian populations. This study tested 12 PIP5K2A SNPs for association with schizophrenia in a sample of 152 sib‐pair families of Indonesian descent. All SNPs had previously been tested for association with schizophrenia in a German family sample by Schwab et al. [2006; Mol Psychiatry] and seven SNPs were nominally associated with schizophrenia in this previous study. The purpose of the study was to examine whether previously implicated PIP5K2A variants influence susceptibility to schizophrenia in populations of non‐European descent. No single markers showed nominal association with schizophrenia in this Indonesian family sample, however multi‐marker haplotypes including a previously associated exonic SNP marker revealed nominally significant association (P = 0.03). Power to detect association was greater than 80% for all previously implicated variants except for rs11013052, where power was greatly reduced due to the low minor allele frequency of this marker in the Indonesian sample. An explorative study combining the results of this study with those of our previous study indicated that rs11013052 was significantly associated with schizophrenia in the combined sample (P = 0.002). The results of this study suggest that any contribution of previously implicated DNA variants within the PIP5K2A gene to schizophrenia susceptibility in the Indonesian population is only minor.