Initial Genome Scan of the NIMH Genetics Initiative Bipolar Pedigrees: Chromosomes 4, 7, 9, 18, 19, 20, and 21q

Abstract

An initial genome scan was performed on 540 individuals from 97 families segregating bipolar disorder, collected through the National Institutes of Mental Health Genetics Initiative. We report here affected-sib-pair (ASP) data on 126 marker loci (approximately 68,000 genotypes) mapping to chromosomes 4, 7, 9, 18, 19, 20, and 21q, under three affection status models. Modest increases in identical-by-descent (IBD) allele sharing were found at the following loci: D4S2397 and D4S391 (P < 0.05) on 4p, D4S1647 (P < 0.05) on 4q, D7S1802 and D7S1869 (low P = 0.01) on 7p, D9S302 (P = 0.004) on 9q, and D20S604 on 20p and D20S173 on 20q (P < 0.05). In addition, five markers on 7q displayed increased IBD sharing (P = 0.046-0.002). Additional ASP analyses on chromosomes 18 and 21q marker data were performed using disease phenotype models defined previously. On chromosome 18, only D18S40 on 18p and D18S70 on 18q yielded a slight elevation in allele sharing (P = 0.02), implying that the reported linkages in these regions were not confirmed. On chromosome 21q, a cluster of markers within an approximately 9 cM interval: D21S1254, D21S65, D21S1440, and D21S1255 exhibited excess allele sharing (P = 0.041-0.008). Multilocus data on overlapping marker quartets, from D21S1265 to D21S1255, which were consistent with increased IBD sharing (P < 0.01, with a low of 0.0009), overlapped a broad interval of excess allele sharing reported previously, increasing support for a susceptibility locus for bipolar disorder on 21q.

Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

“…5 Modest support for linkage to 9q was observed in the NIMH genetics initiative pedigree sample. 48 Our finding at 10q21-24 is consistent with similar findings in another series of US pedigrees 15 and in German 9 and UK-Irish 47 families. Support for linkage to 13q was reported in two separate series of US pedigrees 5,15 and in a large Australian pedigree 49 (though at a more proximal site, on 13q14).…”

“…A more proximal location, on 4q12-13, was reported in UK-Irish families. 47 Possible linkage to 7q was observed in the NIMH genetics initiative pedigree series 48 and in another series of US pedigrees. 5 Modest support for linkage to 9q was observed in the NIMH genetics initiative pedigree sample.…”

“…The putative linkage to 21q22 is supported by other, independent studies. 5,15,48,[50][51][52][53] Two of the regions presumed linked in our study (2p and 13q) have also been implicated in schizophrenia. Support for linkage to schizophrenia on 2p was found in Micronesian pedigrees.…”

An apparently dominant bipolar affective disorder (BPAD) locus on chromosome 20p11.2–q11.2 in a large Turkish pedigree

“…Detera-Wadleigh et al 33 performed a genome-wide scanning by using 540 individuals from 97 families which yielded a weakly increased allele-sharing in affected sibs with markers D20S604 on 20p (P ² 0.05) and D20S173 on 20q (P ² 0.019). No linkage was found in the studies of Pakstis et al 34 and Ewald et al 35 where chromosome 20 markers were exclusively used.…”

Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia

“…LIM is located at 4q22, 16 for which some linkage signal has been detected in bipolar disorder 17 and schizophrenia. 18 Only a few studies revealed the loci in 4q for bipolar disorder [19][20][21] or schizophrenia.…”