Genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar affective disorder

Abstract

Insulin-like growth factor 1 (IGF1) has been shown to have an important role in brain development and function. Studies of IGF1 administration in rodents have shown that it has an anxiolytic and antidepressant effect. A genome-wide association study (GWAS) of the first University College London (UCL) cohort of 506 bipolar affective disorder subjects and 510 controls was carried out. The exons and flanking regions of IGF1 were resequenced, any new polymorphisms found were genotyped in an enlarged UCL sample of 937 cases and 941 controls. GWAS data gave good evidence of allelic and haplotypic association between multiple IGF1 SNP's and bipolar disorder (BD). New polymorphisms were found by resequencing IGF1 region. Data from GWAS and the new markers showed that twelve out of 43 SNPs showed association with BD with the four most significant SNPs having values of 3.7 × 10(-5) , 8.4 × 10(-4) , 2.6 × 10(-4) , and 2.5 × 10(-4) . A 5' promoter microsatellite polymorphism previously correlated with plasma lipoprotein concentration was also associated with BD (P = 0.013). Haplotypic association confirmed association with BD with significance values similar to the single marker SNP values. The marker rs12426318 has also been found to be associated with BD in a second sample. A test of gene wide significance with permutation testing for all markers genotyped at IGF1 was also significant. These data implicate IGF1 as a candidate gene to cause genetic susceptibility to BD.

Current State of Biomarkers in Bipolar Disorder

“…Peripheral levels of IGF-1 were lower in patients with BD compared to patients with schizophrenia [43]. Studies have shown a potential effect of IGF-1 signaling cascade in regulating stress, depression, and hippocampal neurogenesis [43,44]. Therefore, the findings provided regarding the effects of IGF-1 suggest the importance of this NT in the pathophysiology of BD and its potential to be used as a biomarker should be explored in greater detail.…”

Lithium Pharmacogenetics: Where Do We Stand?

“…However, only a few of these markers have been successfully replicated. Promising findings have been reported for Insulin Like Growth Factor 1 (IGF‐1), a growth factor playing an important role in neuronal function and previously associated with BPD [Pereira et al, ]. A genome wide expression study showed increased expression levels of IGF‐1 in lymphoblastoid cell lines (LCLs) from BPD patients responders to lithium (R) compared with nonresponders (NR) and healthy controls [Squassina et al, ].…”

IGF-I biomarker testing in an ethical context

“…As far as the gene-disease relationship is concerned, we need to think of genes as structures that induce protein synthesis and therefore, they are potential tissue markers. As far as the IGF-I gene is concerned, an over-expression of the IGF-I gene in mature tissues is a sign of neoplastic processes, especially brain tumors [111] (Figure 1), and also a sign of other neural pathologies such as Huntington disease [111] (unpublished data) (Figure 2) or depression [112] . On the contrary, the deletion of the IGF-I gene is associated with reduced brain growth and mental retardation [42,113] .…”

“…Moreover, the genetic variation in the IGF-I, IGFBP-3, and SSTR-2 genes (wherein SNPs were genotyped) seems to influence the circulating levels of IGF-I and IGFBP-3 in prostate and breast cancers [126] . Moreover, genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar disorder patients (via haplotype association and a gene test with wide significance of permutation testing for all markers genotyped IGF-1) implicate IGF-1 as a candidate gene that causes genetic susceptibility to this psychiatric disease [112] . The study of IGF-I genetic variation in GH/IGF-1/insulin signaling pathway has demonstrated a potentially new human longevity loci [127] .…”