Study Report

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Basic Info

Reference	Palo, O. M.,2010 PMID: 19851985
Citation	Palo, O. M., P. Soronen, et al. (2010). "Identification of susceptibility loci at 7q31 and 9p13 for bipolar disorder in an isolated population." Am J Med Genet B Neuropsychiatr Genet 153B(3): 723-735.
Disease Type	Bipolar Disorder
Study Design	family-based
Study Type	Genome-wide linkage study and candidate-gene association study
Sample Size	23 late settlement families, consisting of 147 individuals including 68 affected with broad mood disorder for the linkage scan;179 families that included the initial 23 late settlement families consisted of 723 individuals including 298 affected with broad mood disorder for further linkage and association analyses
SNP/Region/Marker Size	6008 SNPs
Predominant Ethnicity	Caucasian
Population	Finnish
Gender	Male/female:74/73 in 23 Late Settlement Families and 344/379 in 179 Families Across Finland Including 23 Late Settlement Families

Detail Info

Sample Diagnosis	DSM and ICD-8
Sample Status	For the linkage scan we chose 23 late settlement families, consisting of 147 individuals from 21 nuclear families and two extended families. The largest extended family consisted of four generations with 18 affected subjects. The study sample included 68 affected individuals with a diagnosis of broadmood disorder, that is, bipolar disorder type I, II, or not otherwise specified, manic type of schizoaffective psychosis, cyclothymia, or recurrent depression. Broad mood disorder phenotype was used because unipolar disorder is the most common disorder in family members of individuals with bipolar disorder. Of unipolar disorder, 12-41% patients eventually develop mania or hypomania [Akiskal et al., 1995; Goldberg et al., 2001]. All 23 families were selected according to the birthplaces of the grandparents so that at least one grandparent from each family originated from the late settlement region of Finland and that in each family there were at least two affected siblings. The families originating from the late settlement region were prioritized in selection. There was an overlap of 14 families with the previous genome-wide linkage scan [Ekholm et al., 2003] and the remaining nine families that were not included in the previous scan fulfill nowthe selection criteria by having at least two siblings affected. For further linkage and association analyses, we used all available families ascertained for bipolar disorder, consisting of a set of 179 families that included the initial 23 late settlement families. The set of 179 families consisted of 723 individuals including 298 affected with broad mood disorder, and altogether 69 families had two or more affected individuals withDNAsample available. In addition, the set of 179 families comprised 44 dizygotic twins (with broadmood disorder n=25) from 29 twin pairs and 6monozygotic twins (with broad mood disorder n=6) from 6 twin pairs, for which the detailed ascertainment strategy and sample collection has been described elsewhere [Kieseppa et al., 2004]. The diagnoses of individuals of 21 BPD families of 41 families included in previous bipolar genome-wide linkage scan analyses [Ekholm et al., 2003] were ascertained and updated in 2003 by using SCID [Spitzer et al., 1997; Antila et al., 2007], revealing altogether 30 changes of diagnosis. Twenty unknown cases were ascertained to have bipolar disorder or recurrent major depressive disorder (rMDD). Ten cases of broad type bipolar disorder including bipolar disorder type I (BPI), bipolar disorder type II (BPII), bipolar disorder not otherwise specified (BPNOS), cyclothymia, and rMDD changed to schizophrenia or other non-bipolar psychosis.
Technique	genotyping(Illumina Linkage Panel IV (6K) Array and Sequenom's MassARRAY System and iPLEX chemistry)
Statistical Method	Two-point parametric LOD scores were calculated for the autosomal markers using the AUTOGSCAN 1.0 program[Hiekkalinna,1999] which automates the use of the ANALYZE package [Lathrop and Lalouel, 1984].Multipoint non-parametric linkage (NPL) analyses and haplotype analyses were conducted only for the regions showing highest genome-wide significance using the Genehunter version v2.1_r6 program [Kruglyak et al., 1996]
Result Summary	We detected genome-wide significant evidence for linkage of mood disorder (bipolar disorder type I, II, or not otherwise specified, manic type of schizoaffective psychosis, cyclothymia, or recurrent depression) to chromosomes 7q31 (LOD = 3.20) and 9p13.1 (LOD = 4.02). Analyzing the best markers on the complete set of 179 Finnish bipolar families supported the findings on chromosome 9p13 (maximum LOD score of 3.02 at position 383 Mb, immediately upstream of the centromere). This region harbors several interesting candidate genes, including contactin associated protein-like 3 (CNTNAP3) and aldehyde dehydrogenase 1 (ALDH1B1). For the 7q31 locus, only one extended pedigree and ten families originating from the same late settlement region in North-Eastern Finland provided evidence for linkage, suggesting that a gene predisposing to bipolar disorder is enriched in that region. Candidate genes of interest in this locus include potassium-voltage-gated channel, member 2 (KCND2) and calcium-dependent activator protein for secretion 2 (CADPS2). The loci on the centromeric region of 9p13 and the telomeric region of 7q31 may represent susceptibility loci for mood disorder in the Finnish population.

Haplotypes reported by this study for BD (count: 78)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs720974 - rs1414237	A-G	9p22.2-9q21.13	Haplotypic association:Z-score=1.746, FBAT P-value = 0.08	No significant association was found . No significant association was found .	Negative
rs757099 - rs1220087	A-G	9p22.2-9q21.13	Haplotypic association:Z-score=-1.978, FBAT P-value = 0.047	Significant association was found. Significant association was found.	Positive
rs944700 - rs1359885	G-C	9p22.2-9q21.13	Haplotypic association:Z-score=-1.585, FBAT P-value = 0.113	No significant association was found . No significant association was found .	Negative
rs12217 - rs1320393	G-A	AASS, SLC13A1	Haplotypic association:Z-score=1.54, FBAT P-value = 0.123	No significant association was found . No significant association was found .	Negative
rs263645 - rs960232	T-A	9p22.2-9q21.13	Haplotypic association:Z-score=-1.713, FBAT P-value = 0.086	No significant association was found . No significant association was found .	Negative
rs560764 - rs1018254	C-G	9p22.2-9q21.13	Haplotypic association:Z-score=1.234, FBAT P-value = 0.217	No significant association was found . No significant association was found .	Negative
rs716933 - rs1004604	T-A	9p22.2-9q21.13	Haplotypic association:Z-score=-2.655, FBAT P-value = 0.007	Significant association was found. Significant association was found.	Positive
rs717081 - rs1332184	G-G	9p22.2-9q21.13	Haplotypic association:Z-score=1.178, FBAT P-value = 0.238	No significant association was found . No significant association was found .	Negative
rs1332677 - rs2169325	G-C	9p22.2-9q21.13	Haplotypic association:Z-score=-1.482, FBAT P-value = 0.138	No significant association was found . No significant association was found .	Negative
rs1404195 - rs1570637	A-A	9p22.2-9q21.13	Haplotypic association:Z-score=1.322, FBAT P-value = 0.186	No significant association was found . No significant association was found .	Negative
rs1412340 - rs288886	G-A	9p22.2-9q21.13	Haplotypic association:Z-score=2.404, FBAT P-value = 0.016	Significant association was found. Significant association was found.	Positive
rs1475656 - rs1412340	A-A	9p22.2-9q21.13	Haplotypic association:Z-score=-2.063, FBAT P-value = 0.039	Significant association was found. Significant association was found.	Positive
rs916691 - rs1013920	T-C	7q22.2-7q31.33	Haplotypic association:Z-score=1.894, FBAT P-value = 0.058	No significant association was found . No significant association was found .	Negative
rs1004604 - rs987187	A-G	9p22.2-9q21.13	Haplotypic association:Z-score=-2.101, FBAT P-value = 0.035	Significant association was found. Significant association was found.	Positive
rs1018254 - rs1475656	G-T	9p22.2-9q21.13	Haplotypic association:Z-score=1.012, FBAT P-value = 0.311	No significant association was found . No significant association was found .	Negative
rs1332184 - rs720974	G-C	9p22.2-9q21.13	Haplotypic association:Z-score=0.716, FBAT P-value = 0.474	No significant association was found . No significant association was found .	Negative
rs885451 - rs944700	G-A	DNAJB5	Haplotypic association:Z-score=1.823, FBAT P-value = 0.068	No significant association was found . No significant association was found .	Negative
rs885993 - rs1896887	G-G	CFTR	Haplotypic association:Z-score=-1.328, FBAT P-value = 0.184	No significant association was found . No significant association was found .	Negative
rs1327063 - rs702223	C-C	ELAVL2	Haplotypic association:Z-score=-2.184, FBAT P-value = 0.028	Significant association was found. Significant association was found.	Positive
rs1476517 - rs7817	G-G	DOCK4 IFRD1	Haplotypic association:Z-score=1.419, FBAT P-value = 0.155	No significant association was found . No significant association was found .	Negative
rs1360590 - rs1327063	A-C	CDKN2B-AS1	Haplotypic association:Z-score=-1.709, FBAT P-value = 0.087	No significant association was found . No significant association was found .	Negative
rs41261 - rs176481	A-G	CDHR3	Haplotypic association:Z-score=2.768, FBAT P-value = 0.005	Significant association was found. Significant association was found.	Positive
rs1896887 - rs38831	G-C	CFTR	Haplotypic association:Z-score=1.295, FBAT P-value = 0.195	No significant association was found . No significant association was found .	Negative
rs1414237 - rs1360590	G-G	CDKN2B-AS1	Haplotypic association:Z-score=1.392, FBAT P-value = 0.163	No significant association was found . No significant association was found .	Negative
rs671018 - rs855543	G-A	TOPORS-AS1, NDUFB6	Haplotypic association:Z-score=-2.776, FBAT P-value = 0.005	Significant association was found. Significant association was found.	Positive
rs288886 - rs671018	G-G	TOPORS-AS1, NDUFB6	Haplotypic association:Z-score=-2.202, FBAT P-value = 0.027	Significant association was found. Significant association was found.	Positive
rs234 - rs41261	A-A	CDHR3	Haplotypic association:Z-score=2.688, FBAT P-value = 0.007	Significant association was found. Significant association was found.	Positive
rs9103 - rs994367	A-A	C9orf72, LINGO2	Haplotypic association:Z-score=1.794, FBAT P-value = 0.072	No significant association was found . No significant association was found .	Negative
rs2076902 - rs748530	G-G	ADAMTSL1, SLC24A2	Haplotypic association:Z-score=0.343, FBAT P-value = 0.731	No significant association was found . No significant association was found .	Negative
rs960232 - rs2076902	A-G	ADAMTSL1	Haplotypic association:Z-score=-1.288, FBAT P-value = 0.197	No significant association was found . No significant association was found .	Negative
rs868053 - rs12217	A-G	CPED1, AASS	Haplotypic association:Z-score=2.013, FBAT P-value = 0.044	Significant association was found. Significant association was found.	Positive
rs846427 - rs868053	A-G	CPED1	Haplotypic association:Z-score=-1.368, FBAT P-value = 0.171	No significant association was found . No significant association was found .	Negative
rs342296 - rs1476878	G-G	PRKAR2B	Haplotypic association:Z-score=2.918, FBAT P-value = 0.003	Significant association was found. Significant association was found.	Positive
rs257376 - rs1858929	G-A	PRKAR2B, SLC26A4	Haplotypic association:Z-score=-1.605, FBAT P-value = 0.108	No significant association was found . No significant association was found .	Negative
rs1414944 - rs1889915	A-G	PIP5K1B, TRPM3	Haplotypic association:Z-score=0.801, FBAT P-value = 0.423	No significant association was found . No significant association was found .	Negative
rs1476878 - rs257376	G-A	PRKAR2B	Haplotypic association:Z-score=2.409, FBAT P-value = 0.016	Significant association was found. Significant association was found.	Positive
rs987187 - rs923784	G-G	PGM5	Haplotypic association:Z-score=-0.811, FBAT P-value = 0.417	No significant association was found . No significant association was found .	Negative
rs2026349 - rs1414944	A-G	PIP5K1B	Haplotypic association:Z-score=-0.844, FBAT P-value = 0.398	No significant association was found . No significant association was found .	Negative
rs41736 - rs885993	G-C	MET, CFTR	Haplotypic association:Z-score=1.557, FBAT P-value = 0.119	No significant association was found . No significant association was found .	Negative
rs923784 - rs2026349	G-C	PGM5	Haplotypic association:Z-score=0.92, FBAT P-value = 0.357	No significant association was found . No significant association was found .	Negative
rs994367 - rs560764	A-C	LINGO2	Haplotypic association:Z-score=1.306, FBAT P-value = 0.191	No significant association was found . No significant association was found .	Negative
rs2056865 - rs41736	G-G	MET	Haplotypic association:Z-score=0.826, FBAT P-value = 0.408	No significant association was found . No significant association was found .	Negative
rs719530 - rs214459	C-A	IMMP2L	Haplotypic association:Z-score=1.81, FBAT P-value = 0.07	No significant association was found . No significant association was found .	Negative
rs37742 - rs1476517	A-A	IMMP2L DOCK4	Haplotypic association:Z-score=0.639, FBAT P-value = 0.523	No significant association was found . No significant association was found .	Negative
rs214459 - rs214468	A-G	IMMP2L	Haplotypic association:Z-score=1.304, FBAT P-value = 0.192	No significant association was found . No significant association was found .	Negative
rs214468 - rs37742	A-A	IMMP2L	Haplotypic association:Z-score=0.639, FBAT P-value = 0.523	No significant association was found . No significant association was found .	Negative
rs702223 - rs1332677	C-A	ELAVL2	Haplotypic association:Z-score=-1.342, FBAT P-value = 0.179	No significant association was found . No significant association was found .	Negative
rs7817 - rs43077	A-G	IFRD1	Haplotypic association:Z-score=-1.958, FBAT P-value = 0.05	No significant association was found . No significant association was found .	Negative
rs855543 - rs471371	G-A	UBE2R2	Haplotypic association:Z-score=2.099, FBAT P-value = 0.035	Significant association was found. Significant association was found.	Positive
rs2169325 - rs1128957	C-A	TUSC1	Haplotypic association:Z-score=-1.505, FBAT P-value = 0.132	No significant association was found . No significant association was found .	Negative
rs1128957 - rs757099	C-A	TUSC1	Haplotypic association:Z-score=-1.505, FBAT P-value = 0.132	No significant association was found . No significant association was found .	Negative
rs1889915 - rs1074670	G-G	TRPM3	Haplotypic association:Z-score=1.73, FBAT P-value = 0.083	No significant association was found . No significant association was found .	Negative
rs1074670 - rs1404195	G-A	TRPM3	Haplotypic association:Z-score=2.147, FBAT P-value = 0.031	Significant association was found. Significant association was found.	Positive
rs1555454 - rs9103	A-G	TEK, C9orf72	Haplotypic association:Z-score=0.434, FBAT P-value = 0.664	No significant association was found . No significant association was found .	Negative
rs666478 - rs1555454	G-A	TEK	Haplotypic association:Z-score=3.218, FBAT P-value = 0.001	Significant association was found. Significant association was found.	Positive
rs1220087 - rs666478	A-G	TEK	Haplotypic association:Z-score=4.405, FBAT P-value = 0.00001	Significant association was found. Significant association was found.	Positive
rs1858929 - rs2028030	G-G	SLC26A4	Haplotypic association:Z-score=0.504, FBAT P-value = 0.614	No significant association was found . No significant association was found .	Negative
rs748530 - rs717081	G-A	SLC24A2	Haplotypic association:Z-score=0.657, FBAT P-value = 0.511	No significant association was found . No significant association was found .	Negative
rs1880180 - rs1121030	A-G	SLC13A1	Haplotypic association:Z-score=0.592, FBAT P-value = 0.554	No significant association was found . No significant association was found .	Negative
rs1320393 - rs1880180	G-A	SLC13A1	Haplotypic association:Z-score=-1.204, FBAT P-value = 0.228	No significant association was found . No significant association was found .	Negative
rs735741 - rs1138374	G-G	SHB, MIR3159	Haplotypic association:Z-score=0.308, FBAT P-value = 0.758	No significant association was found . No significant association was found .	Negative
rs1138374 - rs716933	G-A	SHB	Haplotypic association:Z-score=3.23, FBAT P-value = 0.001	Significant association was found. Significant association was found.	Positive
rs954779 - rs735741	G-A	RNF38, SHB, MIR3159	Haplotypic association:Z-score=-0.891, FBAT P-value = 0.373	No significant association was found . No significant association was found .	Negative
rs1359885 - rs954779	C-G	RNF38	Haplotypic association:Z-score=-0.543, FBAT P-value = 0.586	No significant association was found . No significant association was found .	Negative
rs471371 - rs885451	G-C	UBE2R2, DNAJB5	Haplotypic association:Z-score=-1.808, FBAT P-value = 0.07	No significant association was found . No significant association was found .	Negative
rs2040587 - rs2056865	A-G	7q22.2-7q31.33	Haplotypic association:Z-score=-2.183, FBAT P-value = 0.029	Significant association was found. Significant association was found.	Positive
rs2028030 - rs916691	A-A	7q22.2-7q31.33	Haplotypic association:Z-score=-0.967, FBAT P-value = 0.333	No significant association was found . No significant association was found .	Negative
rs1860487 - rs648619	A-A	7q22.2-7q31.33	Haplotypic association:Z-score=-1.098, FBAT P-value = 0.272	No significant association was found . No significant association was found .	Negative
rs1833083 - rs996867	A-A	7q22.2-7q31.33	Haplotypic association:Z-score=0.608, FBAT P-value = 0.542	No significant association was found . No significant association was found .	Negative
rs887882 - rs1024761	G-G	7q22.2-7q31.33	Haplotypic association:Z-score=1.778, FBAT P-value = 0.075	No significant association was found . No significant association was found .	Negative
rs648619 - rs1833083	G-G	7q22.2-7q31.33	Haplotypic association:Z-score=-1.008, FBAT P-value = 0.313	No significant association was found . No significant association was found .	Negative
rs43077 - rs2040587	G-G	7q22.2-7q31.33	Haplotypic association:Z-score=2.222, FBAT P-value = 0.026	Significant association was found. Significant association was found.	Positive
rs38831 - rs1510504	C-G	7q22.2-7q31.33	Haplotypic association:Z-score=1.694, FBAT P-value = 0.09	No significant association was found . No significant association was found .	Negative
rs1013920 - rs719530	A-A	7q22.2-7q31.33	Haplotypic association:Z-score=-0.952, FBAT P-value = 0.341	No significant association was found . No significant association was found .	Negative
rs176481 - rs887882	G-A	7q22.2-7q31.33	Haplotypic association:Z-score=-1.659, FBAT P-value = 0.097	No significant association was found . No significant association was found .	Negative
rs1510504 - rs846427	A-C	7q22.2-7q31.33	Haplotypic association:Z-score=-1.224, FBAT P-value = 0.221	No significant association was found . No significant association was found .	Negative
rs1121030 - rs1860487	A-G	7q22.2-7q31.33	Haplotypic association:Z-score=0.592, FBAT P-value = 0.554	No significant association was found . No significant association was found .	Negative
rs1024761 - rs342296	A-G	7q22.2-7q31.33	Haplotypic association:Z-score=3.538, FBAT P-value = 0.0004	Significant association was found. Significant association was found.	Positive

Regions reported by this study for BD (count: 7)

Region	Statistical Values	Author Comments	Result Category
7q31.31	For marker rs1510504: In initial families(n = 32), linkage analysis: dominant model, HLOD = 0.43, LOD = 0.71, recessive model, HLOD = 3.2, LOD = 3.2; association analysis: FBAT P-value = 0.569; in families including 23 initial families(n = 179), linkage analysis: dominant model, HLOD = 0.23, LOD = 0.38, recessive model, HLOD = 1.39, LOD = 1.39; association analysis: FBAT P-value = 0.885	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
7q22.3	In initial families(n = 32), linkage analysis: dominant model, HLOD = 0.53, LOD = 0.53, recessive model, HLOD = 1.58, LOD = 1.94; association analysis: FBAT P-value = 0.0001; in families including 23 initial families(n = 179), linkage analysis: dominant model, HLOD = 0.07, LOD = 0.07, recessive model, HLOD = 0.36, LOD = 0.77; association analysis: FBAT P-value = 0.089	Significant linkage was found in this region for BPI. Significant linkage was found in this region for BPI.	Positive
9q13	For marker rs2026349: In initial families(n = 32), linkage analysis: dominant model, HLOD = 2.82, LOD = 2.96, recessive model, HLOD = 1.22, LOD = 1.23; association analysis: FBAT P-value = 0.799; in families including 23 initial families(n = 179), linkage analysis: dominant model, HLOD = 0, LOD = 0, recessive model, HLOD = 0.18, LOD = 0.18; association analysis: FBAT P-value = 0.111	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend
9p21.3	In initial families(n = 32), linkage analysis: dominant model, HLOD = 1.97, LOD = 1.97, recessive model, HLOD = 0.33, LOD = 0.52; association analysis: FBAT P-value = 0.815; in families including 23 initial families(n = 179), linkage analysis: dominant model, HLOD = 0.3, LOD = 0.3, recessive model, HLOD = 0.01, LOD = 0.01; association analysis: FBAT P-value = 0.607	No significant linkage was found in this region. No significant linkage was found in this region.	Negative
9p21.1	In initial families(n = 32), linkage analysis: dominant model, HLOD = 2.42, LOD = 2.42, recessive model, HLOD = 1.94, LOD = 2.18; association analysis: FBAT P-value = 0.043; in families including 23 initial families(n = 179), linkage analysis: dominant model, HLOD = 0.54, LOD = 0.94, recessive model, HLOD = 0.18, LOD = 0.18; association analysis: FBAT P-value = 0.339	Significant linkage was found in this region for BPI. Significant linkage was found in this region for BPI.	Positive
9p13.1	For marker rs716933: In initial families(n = 32), linkage analysis: dominant model, HLOD = 4.02, LOD = 4.02, recessive model, HLOD = 1.77, LOD = 1.77; association analysis: FBAT P-value = 0.064; in families including 23 initial families(n = 179), linkage analysis: dominant model, HLOD = 2.91, LOD = 3.06, recessive model, HLOD = 1.37, LOD = 1.37; association analysis: FBAT P-value = 0.306	Significant linkage was found in this region for BPI. Significant linkage was found in this region for BPI.	Positive
7q31.32	In initial families(n = 32), linkage analysis: dominant model, HLOD = 2.06, LOD = 2.06, recessive model, HLOD = 1.93, LOD = 1.93; association analysis: FBAT P-value = 0.773; in families including 23 initial families(n = 179), linkage analysis: dominant model, HLOD = 0.59, LOD = 0.63, recessive model, HLOD = 0.69, LOD = 0.69; association analysis: FBAT P-value = 0.398	Suggestive linkage was found in this region. Suggestive linkage was found in this region.	Trend