Kremeyer, B.; (2008) Genetic analysis of neuropsychiatric disorders in a South American population isolate. Doctoral thesis , University of London.

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Abstract

Bipolar disorder (BP) and schizophrenia are severe neuropsychiatric conditions that are among the leading causes of morbidity and chronic disability world-wide. Both conditions are characterised by a substantial genetic heterogeneity, which has complicated the search for susceptibility loci. One strategy to tackle this difficulty lies in the study of population isolates that are characterised by a reduced genetic heterogeneity. In this thesis, I have therefore conducted genetic studies of BP and schizophrenia in the well-characterised South American population isolate of Antioquia, Colombia. Our group has recently reported the results of a linkage scan of six Antioquian families segregating severe BP. Here, I performed a follow-up study of a candidate region on chromosome 5q33. I sequenced the CLINT 1 gene, a functional candidate that has also been implicated in schizophrenia, in affecteds from four BP pedigrees from the original linkage study and identified three single base pair variants, all of which had been previously described. A transmission distortion test of one of these variants, rs 11955293, in a sample of 176 unrelated BP patients from Antioquia and their parents found no evidence of association with BP. Although these results do not rule out a minor effect of the CLINT1 gene on susceptibility to the disorder in Antioquia, other loci are likely to be of greater significance. This includes other genes on chromosome 5q33, but also other candidate regions in the genome. To further explore the latter possibility, I conducted a whole-genome linkage scan in an additional nine pedigrees with severe BP from Antioquia and analysed the obtained genotype data jointly with that of the initial linkage scan. Using parametric and non-parametric linkage approaches, I explored three different diagnostic models: a narrow model including only BP type I (BPI) as affected a model including BPI and II and major unipolar depression and a third model including only individuals who had experienced psychosis as affected. This second linkage scan found evidence for a number of candidate regions, including chromosome 13q33 for BPI, chromosomes lpl3-31 and lq25-31 for mood disorders, chromosome 12ct-ql4 for mood disorders, and chromosomes 2q24-31 and 16pl2 for psychosis. Encouragingly, many of these loci had previously been pinpointed as BP susceptibility loci in other populations on the other hand, we also identified a novel locus on chromosome 12q. While the use of population isolates can help decrease the genetic heterogeneity of a complex disease, complementary strategies can be used to reduce this heterogeneity even further. In studying the NOS1AP gene, a functional candidate on chromosome lq23 that is involved in glutamatergic neurotransmission, in a sample of 102 unrelated Antioquian schizophrenia patients and their parents, I have therefore used both categorical and dimensional approaches to the disease phenotype. In the categorical approach, I conducted an analysis for association between the NOS1AP gene and DSM-IV schizophrenia by TDT. For the dimensional approach, two clinical scales measuring positive and negative symptoms, SANS and SAPS, were applied to all patients and dimensional scores were obtained from these scales by factors analysis. I then performed quantitative TDT analysis of the dimensional scores. My analyses found association to both DSM-IV schizophrenia and a clinical dimension capturing negative symptoms, in line with a role of NOS1AP in glutamatergic neurotransmission. The results of these analyses also underline the usefulness of a dimensional approach in psychiatric genetics.

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