Study Report

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Basic Info

Reference	Pereira, A. C.,2011 PMID: 21302346
Citation	Pereira, A. C., A. McQuillin, et al. (2011). "Genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar affective disorder." Am J Med Genet B Neuropsychiatr Genet 156(2): 177-187.
Disease Type	Bipolar Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	506 bipolar affective disorder subjects and 510 controls for GWAS,937 cases and 941 controls for IGF1 gene association analysis
SNP/Region/Marker Size	37 SNPs
Predominant Ethnicity	Caucasian
Population	Irish, Welsh, Scottish and English

Detail Info

Sample Diagnosis	RDC
Sample Status	The 506 bipolar research subjects and the first cohort of 510 comparison subjects were selected if both their parents and all four grandparents were of Irish, Welsh, Scottish, or English ancestry as defined by an ancestry checklist. Subjects were also included if one of the four grandparents was of European ancestry before the 2004 EU enlargement.All these research subjects were found to have bipolar I diagnoses with psychotic symptoms according to Research Diagnostic Criteria [Spitzer et al., 1978].The 510 comparison subjects were found to be normal with the SADS-L interview and had no personal or first degree family history of any mental disorder. A further 480 unscreened normal comparison subjects were also used in the later stage of the tests of association after the resequencing had been carried out.DNA was obtained from blood samples for the first 506 cases and then from saliva for the second sample of 431 cases.This second cohort of UCL bipolar cases was also selected under the same ancestry checklist as previously, where only if both their parents and all four grandparents were of Irish, Welsh, Scottish, or English ancestry they would be included in our study.
Technique	PCR and sequencing
Statistical Method	Genotypic and allelic associations for SNPs were tested using X² tests. Microsatellite data were analyzed for allelic association with BD using CLUMP which employs an empirical Monte Carlo test.Tests of haplotypic association were carried out using GENECOUNTING.
Result Summary	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 x 10(-5) , 8.4 x 10(-4) , 2.6 x 10(-4) , and 2.5 x 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.

SNPs reported by this study for BD (count: 47)

SNP	Related Gene(s)	Allele Change	Statistical Values	Author Comments	Result Category
rs753479	IGF1	A/G	X² tests: X²=1.803, P-value = 0.179	No significant association was observed. No significant association was observed.	Negative
rs75244810	IGF1	T/G	X² tests: X²=0.753, P-value = 0.385	No significant association was observed. No significant association was observed.	Negative
rs7313075	IGF1		Tests Carried Out With PLINK in the 2, 000 Case/Control UCL Bipolar Sample, Dominance test, X²=13.8, P-value = 0.000203, Recessitivity test, X²=1.371, P-value = 0.242, Genotypic test, X²=18.3, P-value = 0.000106, Trend test, X²=8.987, P-value = 0.003	Significant association was found, the effect of IGF1 on BD ...... Significant association was found, the effect of IGF1 on BD was dominant. More...	Positive
rs703548	IGF1	G/A	X² tests: X²=4.04, P-value = 0.044; Tests Carried Out With PLINK in the 2, 000 Case/Control UCL Bipolar Sample, Dominance test, X²=5.4, P-value = 0.02, Recessitivity test, X²=0.044, P-value = 0.834, Genotypic test, X²=5.94, P-value = 0.051, Trend test, X²=4.186, P-value = 0.041	Significant association was found . Significant association was found .	Positive
rs855288	IGF1	C/G	X² tests: X²=3.71, P-value = 0.054; Tests Carried Out With PLINK in the 2, 000 Case/Control UCL Bipolar Sample, Dominance test, X²=5.3, P-value = 0.021, Recessitivity test, X²=0.188, P-value = 0.664, Genotypic test, X²=6.251, P-value = 0.044, Trend test, X²=3.816, P-value = 0.051	Significant association was found, the effect of IGF1 on BD ...... Significant association was found, the effect of IGF1 on BD was dominant. More...	Positive
rs7978777	IGF1	C/A	X² tests: X²=0.11, P-value = 0.74	No significant association was observed. No significant association was observed.	Negative
rs7955640	IGF1		Tests Carried Out With PLINK in the 2, 000 Case/Control UCL Bipolar Sample, Dominance test, X²=4.151, P-value = 0.042, Recessitivity test, X²=0.162, P-value = 0.687, Genotypic test, X²=4.187, P-value = 0.123, Trend test, X²=3.416, P-value = 0.065	Significant association was found, the effect of IGF1 on BD ...... Significant association was found, the effect of IGF1 on BD was dominant. More...	Positive
rs78352613	IGF1	G/T	X² tests: X²=7.49, P-value = 0.006	Significant association was found . Significant association was found .	Positive
rs978458	IGF1	G/A	X² tests: X²=0.011, P-value = 0.918	No significant association was observed. No significant association was observed.	Negative
rs9308315	IGF1	T/A	X² tests: X²=0.016, P-value = 0.899	No significant association was observed. No significant association was observed.	Negative
rs860598	IGF1	G/C	X² tests: X²=1.292, P-value = 0.256	No significant association was observed. No significant association was observed.	Negative
rs10860857	IGF1	C/A	Tests Carried Out With PLINK in the 2, 000 Case/Control UCL Bipolar Sample, Dominance test, X²=4.535, P-value = 0.033, Recessitivity test, X²=0.153, P-value = 0.696, Genotypic test, X²=4.604, P-value = 0.1, Trend test, X²=3.044, P-value = 0.081	Significant association was found, the effect of IGF1 on BD ...... Significant association was found, the effect of IGF1 on BD was dominant. More...	Positive
rs10860860	IGF1	T/A	X² tests: X²=1.385, P-value = 0.239	No significant association was observed. No significant association was observed.	Negative
rs1019731	IGF1	G/T	X² tests: X²=0.008, P-value = 0.929	No significant association was observed. No significant association was observed.	Negative
rs10745940	IGF1	C/T	X² tests: X²=0.008, P-value = 0.93	No significant association was observed. No significant association was observed.	Negative
rs10860869	IGF1	A/T	X² tests: X²=0.375, P-value = 0.54	No significant association was observed. No significant association was observed.	Negative
rs10860864	IGF1	C/T	X² tests: X²=0.184, P-value = 0.668	No significant association was observed. No significant association was observed.	Negative
rs11111272	IGF1	G/C	X² tests: X²=0.014, P-value = 0.907	No significant association was observed. No significant association was observed.	Negative
rs11111243	IGF1	C/G	X² tests: X²=1.713, P-value = 0.191	No significant association was observed. No significant association was observed.	Negative
rs12309723	IGF1	A/C	X² tests: X²=3.969, P-value = 0.046	Significant association was found . Significant association was found .	Positive
rs11829367	IGF1	G/A	X² tests: X²=0.239, P-value = 0.625	No significant association was observed. No significant association was observed.	Negative
rs12426318	IGF1		Tests Carried Out With PLINK in the 2, 000 Case/Control UCL Bipolar Sample, Dominance test, X²=20.19, P-value = 0.00000701, Recessitivity test, X²=0.07, P-value = 0.792, Genotypic test, X²=20.57, P-value = 0.0000342, Trend test, X²=17.82, P-value = 0.0000243	Significant association was found, the effect of IGF1 on BD ...... Significant association was found, the effect of IGF1 on BD was dominant. More...	Positive
rs12423791	IGF1	C/G	X² tests: X²=13.334, P-value = 0.0003	Significant association was found . Significant association was found .	Positive
rs17439974	IGF1		Tests Carried Out With PLINK in the 2, 000 Case/Control UCL Bipolar Sample, Dominance test, X²=5.828, P-value = 0.016, Recessitivity test, X²=0.648, P-value = 0.421, Genotypic test, X²=5.841, P-value = 0.054, Trend test, X²=4.972, P-value = 0.026	Significant association was found, the effect of IGF1 on BD ...... Significant association was found, the effect of IGF1 on BD was dominant. More...	Positive
rs12821878	IGF1	G/A	X² tests: X²=1.585, P-value = 0.208	No significant association was observed. No significant association was observed.	Negative
rs2072592	IGF1	G/A	X² tests: X²=11.152, P-value = 0.001	Significant association was found . Significant association was found .	Positive
rs17727841	IGF1		X² tests: X²=0.039, P-value = 0.843	No significant association was observed. No significant association was observed.	Negative
rs2195243	IGF1	G/C	X² tests: X²=0.065, P-value = 0.799	No significant association was observed. No significant association was observed.	Negative
rs2114913	IGF1	A/G	X² tests: X²=3.253, P-value = 0.071	No significant association was observed. No significant association was observed.	Negative
rs2607983	IGF1	A/G	Tests Carried Out With PLINK in the 2, 000 Case/Control UCL Bipolar Sample, Dominance test, X²=8.318, P-value = 0.004, Recessitivity test, X²=0.074, P-value = 0.786, Genotypic test, X²=8.44, P-value = 0.015, Trend test, X²=7.323, P-value = 0.007	Significant association was found, the effect of IGF1 on BD ...... Significant association was found, the effect of IGF1 on BD was dominant. More...	Positive
rs2373721	IGF1	G/C	X² tests: X²=1.308, P-value = 0.253	No significant association was observed. No significant association was observed.	Negative
rs2607986	IGF1	T/G	X² tests: X²=2.228, P-value = 0.136	No significant association was observed. No significant association was observed.	Negative
rs2946831	IGF1	A/C	X² tests: X²=1.419, P-value = 0.234	No significant association was observed. No significant association was observed.	Negative
rs35762	IGF1	G/A	X² tests: X²=2.02, P-value = 0.155	No significant association was observed. No significant association was observed.	Negative
rs35765	IGF1	C/A	X² tests: X²=5.257, P-value = 0.022	Significant association was found . Significant association was found .	Positive
rs4764695	IGF1	T/C	X² tests: X²=1.331, P-value = 0.249	No significant association was observed. No significant association was observed.	Negative
rs4764698	IGF1	G/C	X² tests: X²=13.375, P-value = 0.0003	Significant association was found . Significant association was found .	Positive
rs55650342	IGF1	G/C	X² tests: X²=0.299, P-value = 0.583	No significant association was observed. No significant association was observed.	Negative
rs5742612	IGF1	T/C	X² tests: X²=0.753, P-value = 0.385	No significant association was observed. No significant association was observed.	Negative
rs5742615	IGF1	G/T	X² tests: X²=17.006, P-value = 0.00003726	Significant association was found . Significant association was found .	Positive
rs5742620	IGF1	C/A	X² tests: X²=3.724, P-value = 0.053	No significant association was observed. No significant association was observed.	Negative
rs5742632	IGF1	A/G	X² tests: X²=1.577, P-value = 0.209	No significant association was observed. No significant association was observed.	Negative
rs5742652	IGF1	C/T	X² tests: X²=0.098, P-value = 0.754	No significant association was observed. No significant association was observed.	Negative
rs5742678	IGF1	C/G	X² tests: X²=0.011, P-value = 0.918	No significant association was observed. No significant association was observed.	Negative
rs5742688	IGF1	G/A	X² tests: X²=7.637, P-value = 0.006	Significant association was found . Significant association was found .	Positive
rs6214	IGF1	G/A	X² tests: X²=0.415, P-value = 0.519	No significant association was observed. No significant association was observed.	Negative
rs703542	IGF1	G/C	X² tests: : X²=4.975, P-value = 0.026; Tests Carried Out With PLINK in the 2, 000 Case/Control UCL Bipolar Sample, Dominance test, X²=6.248, P-value = 0.012, Recessitivity test, X²=0.000161, P-value = 0.99, Genotypic test, X²=6.534, P-value = 0.038, Trend test, X²=5.173, P-value = 0.023	Significant association was found, the effect of IGF1 on BD ...... Significant association was found, the effect of IGF1 on BD was dominant. More...	Positive

Haplotypes reported by this study for BD (count: 2)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
IGF1_(CA)n - rs2195243 - rs12309723	306-G-A	IGF1	Haplotype analysis:likelihood ratio test:global empirical P-value = 0.00068	Significant association was found in global P-value. Significant association was found in global P-value.	Positive
rs11111243 - rs10860857 - rs4764695 - rs10860860 - rs2946831	C-C-C-T-A	IGF1	Haplotype analysis:likelihood ratio test:global empirical P-value = 0.0006	Significant association was found in global P-value. Significant association was found in global P-value.	Positive

Other variants reported by this study for BD (count: 1)

Variant Name	Related Gene	Type	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
IGF1 (CA)n	IGF1	microsatellite	(CA)n repeat		CLUMP empirical test:X²=15.076, P-value = 0.013	Significant association was found. Significant association was found.	Positive

Genes reported by this study for BD (count: 1)