Fine mapping of candidate regions for bipolar disorder provides strong evidence for susceptibility loci on chromosomes 7q

Abstract

Genomewide scans of bipolar disorder (BP) have not produced consistent linkage findings. Follow-up studies using enlarged samples and enhanced marker density can bolster or refute claims of linkage and pave the way to gene discovery. We conducted linkage and association analyses, using a ~3-cM density map of 10 candidate regions, in a large BP pedigree sample (865 individuals from 56 pedigrees). The candidate regions were identified in a previous 10-cM genome-wide scan using a subset of this sample (373 individuals from 40 pedigrees). The present sample consists of the expanded original pedigrees ('core' pedigrees) and 16 additional pedigrees. We obtained experiment-wide significant linkage on chromosome 7q34 (LOD score 3.53, p<0.001), substantially stronger than that observed in the genome-wide scan. Support for linkage was sustained on chromosomes 2p13, 4q31, 8q13, 13q32, 14q21 and 17q11, though at a more modest level. Family-based association analysis was consistent with the linkage results at all regions with linkage evidence, except 4q an 8q, but the results fell short of statistical significance. Three of the previously implicated regions -9q31, 10q21 and 10q24 -showed substantial reduction in evidence of linkage. Our results strongly support 7q34 as a region harboring susceptibility locus for BP. Somewhat lesser, yet notable support was obtained for 2p13, 4q31, 8q13, 13q32, 14q21 and 17q11. These regions could be considered prime candidates for future gene finding efforts.

Advancing biomarker research: utilizing ‘Big Data’ approaches for the characterization and prevention of bipolar disorder

“…Results include, but are not limited to, circadian rhythms (e.g., aryl hydrocarbon receptor nuclear translocator‐like BmaL1 (ARNTL) and RAR‐related orphan receptor B (RORB), neuronal development (e.g., neurotrophic factors and DISC1) , calcium metabolism (e.g., CACNA1C and RASGRP1) , monoamine metabolism (e.g., TPH1 A218C) , mitochondrial function (e.g., POLGI) and cell survival . Notwithstanding, effect sizes for most susceptibility genes are low, results are often inconsistent, and discriminant power is insufficient for clinical utility .…”

“…Several investigations have reported structural, functional, and neurochemical abnormalities in the central nervous system (CNS) of pediatric populations with BD and those identified as at risk . Volumetric studies have reported abnormalities in several regions including, but not limited to, smaller cerebral volumes , enlargement of the striatum, and smaller and larger amygdala volumes .…”

Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome

“…Of note, the GCR locus 5q31 is associated to hypertension99 and linked to bipolar disorder 100. The MCR locus chromosome 4q31.1-31.2 is linked to T2D and MetS101 and to bipolar disorder 102–105106–115…”

“… 100 The MCR locus chromosome 4q31.1-31.2 is linked to T2D and MetS 101 and to bipolar disorder. 102 – 105 MCR and GCR variants affect coping style and depression vulnerability, antidepressants response, stress, and depression endocrine response. 106 – 115 MCR expression is increased in the hypothalamus of diabetic rats 116 and MCR is linked to blood pressure.…”