ABCMdb

PMID: 19944402

Knight HM, Pickard BS, Maclean A, Malloy MP, Soares DC, McRae AF, Condie A, White A, Hawkins W, McGhee K, van Beck M, MacIntyre DJ, Starr JM, Deary IJ, Visscher PM, Porteous DJ, Cannon RE, St Clair D, Muir WJ, Blackwood DH
A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.
Am J Hum Genet. 2009 Dec;85(6):833-46. Epub ., [PubMed]

Sentences

No. Mutations Sentence Comment

91 ABCA13 p.His3609Pro ABCA13 p.Thr4550Ala ABCA13 p.Thr4031Ala ABCA13 p.Arg4843Leu Despite relatively small numbers, three variants (H3609P, T4031A, and T4550A) were significantly more frequent in bipolars than controls and R4843L was more common in schizophrenia (Table 2), although none remained significant after correction for multiple testing of 10 variants in three phenotypes. Login to comment 100 ABCA13 p.Arg4843Cys ABCA13 p.His3609Pro ABCA13 p.Thr4550Ala ABCA13 p.Arg4590Trp ABCA13 p.Thr4031Ala ABCA13 p.Pro4648Ala ABCA13 p.His4262Arg ABCA13 p.Arg4454Cys ABCA13 p.Ile4841Val ABCA13 p.Ser3704Arg ABCA13 p.Leu4047Val ABCA13 p.Arg3604Gln ABCA13 p.Arg4728* ABCA13 p.Leu4464Met All ABCA13 Variants with Provisional dbSNP Identifiers Identified during the Resequencing Discovery Stage of This Study Domain Chr7 Location bp NCBI Build 36.1 Base Change dbSNP Reference AA Change Substitution Type MAF Cases MAF controls Discovery Populationa TMD1 48,382,318 G/A ss136294996 R3604Q missense A: 0.0003 A: 0.0005 case TMD1 48,382,333 A/C ss136295002 H3609P missense C: 0.0085 C: 0.0043 both TMD1 48,382,337 A/C ss136295006 P3610P synonymous C: 0.0096 C: 0.0000 case TMD1 48,382,337 A/T ss136295010 P3610P synonymous T: 0.0048 T: 0.0037 both TMD1 48,382,619 T/G ss136295014 S3704R missense/splice variant G: 0.0003 G: 0.0000 case TMD1 48,384,364 C/T ss136295018 intronic T: 0.0095 T: 0.0160 both TMD1 48,384,474 A/G ss136295022 intronic G: 0.0045 G: 0.0000 case TMD1 48,384,623 T/C ss136295026 intronic C: 0.0048 C: 0.0053 both TMD1 48,398,156 G/A ss136295030 intronic A: 0.0523 nd case TMD1 48,398,232 G/C ss136295034 intronic C: 0.0048 nd case NBD1 48,399,292 C/G ss136295038 L3861L synonymous G: 0.0000 G: 0.0052 control NBD1 48,399,322 T/C ss136295042 T3871T synonymous C: 0.0000 C: 0.0052 control NBD1 48,413,738 C/T ss136295046 intronic T: 0.0092 nd case NBD1 48,420,643 C/T ss136295050 intronic T: 0.1651 T: 0.2067 both NBD1 48,420,683 A/G ss136295054 T4031A missense G: 0.0009 G: 0.0000 case NBD1 48,420,731 C/G ss136295058 L4047V missense (>1% frequency) G: 0.0169 G: 0.0104 both NBD1 48,420,834 C/G ss136295062 intronic G: 0.1651 G: 0.2067 both HDR 48,465,394 T/C ss136295066 P4260P synonymous C: 0.0000 C: 0.0052 control HDR 48,465,399 A/G ss136295070 H4262R missense G: 0.0003 G: 0.0000 case TMD2 48,518,027 C/T ss136295074 R4454C missense (>1% frequency) T: 0.0142 T: 0.0156 both TMD2 48,518,057 C/A ss136295078 L4464M missense (>1% frequency) A: 0.0095 A: 0.0208 both TMD2 48,526,874 A/G ss136295082 T4550A missense A: 0.0056 A: 0.0014 case TMD2 48,526,994 C/T ss136295086 R4590W missense T: 0.0044 T: 0.0019 control TMD2 48,527,112 C/G ss136295090 intronic G: 0.0286 G: 0.0161 both TMD2 48,530,327 C/G ss136295094 P4648A missense G: 0.0000 G: 0.0004 control NBD2 48,534,459 A/G ss136295098 R4707R synonymous G: 0.0500 G: 0.0526 both NBD2 48,534,520 C/T ss136295102 R4728X nonsense T: 0.0025 T: 0.001 case NBD2 48,538,544 C/T ss136295106 intronic T: 0.0000 T: 0.0153 control NBD2 48,538,545 C/T ss136295110 intronic T: 0.0000 T: 0.0052 control NBD2 48,597,311 A/G ss136295114 I4841V missense G: 0.0040 G: 0.0000 case NBD2 48,597,317 C/T ss136295118 R4843C missense T: 0.0050 T: 0.0031 control NBD2 48,604,841 C/A ss136295122 intronic A: 0.0519 A: 0.0789 both The genomic and functional domain location of the variants is displayed together with mutation class and frequency in the discovery set. Login to comment 104 ABCA13 p.Arg4843Cys ABCA13 p.Arg4843Cys ABCA13 p.His3609Pro ABCA13 p.His3609Pro ABCA13 p.Thr4550Ala ABCA13 p.Thr4550Ala ABCA13 p.Arg4590Trp ABCA13 p.Arg4590Trp ABCA13 p.Thr4031Ala ABCA13 p.Thr4031Ala ABCA13 p.Pro4648Ala ABCA13 p.Pro4648Ala ABCA13 p.His4262Arg ABCA13 p.His4262Arg ABCA13 p.Ser3704Arg ABCA13 p.Ser3704Arg ABCA13 p.Arg3604Gln ABCA13 p.Arg3604Gln ABCA13 p.Arg4728* ABCA13 p.Arg4728* The Properties of Ten Rare ABCA13 Variants Genotyped in Large Test Cohorts of Cases and Controls Representation in Discovery Set Representation in Test Set SCZ BP MDD Variant Domain Exon Genomic Position Base Change WT Residue Conservation Residue Change Type SCZ (n ¼ 100) Controls (n ¼ 100) Cases (total) Cases by Diagnosis (Total) Controls (Total) p Value Odds Ratio p Value Odds Ratio p Value Odds Ratio 1 TMD1 33 48,382,318 G/A RH, D, R, M, R3604Q missense 1 0 0 (1666) 0/841 SCZ, 0/494 BP, 0/331 MDD 1 (951) 2 TMD1 33 48,382,333 A/C RH, D, R, M, Ch H3609P missense 3 1 25 (1607) 10/857 SCZ, 10/488 BP, 5/262 MDD 8 (939) 0.334 1.37 0.050 2.43 0.130 2.62 3 TMD1 33 48,382,619 T/G RH, D, R, M, Ch S3704R miss./splice 1 0 0 (1606) 0/851 SCZ, 0/496 BP, 0/259 MDD 0 (939) 4 NBD1 40 48,420,683 A/G RH, D, R, M, Ch T4031A missense 1 0 3 (2072) 0/1019 SCZ, 3/678 BP, 0/365 MDD 0 (2262) 0.012 infinity 5 HDR 43 48,465,399 A/G RH, R, M, Ch H4262R missense 1 0 0 (1717) 0/837 SCZ, 0/562 BP, 0/318 MDD 0 (980) 6 TMD2 52 48,526,874 A/G RH, D, R, Ch T4550A missense 1 0 18 (1608) 9/861 SCZ, 8/482 BP, 1/265 MDD 3 (938) 0.054 3.29 0.0097 5.25 0.63 1.18 7 TMD2 52 48,526,994 C/T RH, D, R, M, Ch R4590W missense 0 1 17 (1846) 6/874 SCZ, 7/622 BP, 4/350 MDD 4 (971) 0.38 1.5 0.087 2.75 0.14 2.78 8 TMD2 53 48,530,327 C/G RH, D, R, M, Ch P4648A missense 0 1 0 (1488) 0/869 SCZ, 0/619 BP 0 (959) 9 NBD2 54 48,534,520 C/T RH, D, R, M, Ch R4728X nonsense 1 0 10 (2058) 4/1004 SCZ, 5/680 BP, 1/374 MDD 5 (2270) 0.370 1.51 0.057 3.35 0.600 1.21 10 NBD2 57 48,597,317 C/T RH, D, R, M, Ch R4843C missense 0 1 19 (1770) 12/815 SCZ, 5/619 BP, 2/336 MDD 6 (1025) 0.047 2.54 0.400 1.38 0.630 1.02 Global significance of all variants by diagnosis (95% CI lower limit shown for odds ratios): 5.70E- 03 1.93 (1.24) 7.42E- 05 2.71 (1.73) 9.66E- 02 1.67 (0.88) Population attributable risk by diagnosis: 2.21% 4.00% 0.02% 838TheAmericanJournalofHumanGenetics85,833-846,December11,2009 Nonparametric single point linkage analysis with MERLIN50 to estimate identity by descent (IBD) between all pairs of affected relatives in the 14 multiply affected families informative for linkage gave a combined Z score of 4.18 and a Kong and Cox51 LOD score of 4.38 (p ¼ 3.5 3 10À6 ), establishing significant linkage of ABCA13 mutations with a ''broad`` phenotype that included cases with schizophrenia, bipolar disorder, and major depression. Login to comment 107 ABCA13 p.Thr4031Ala ABCA13 p.Ser3704Arg ABCA13 p.Arg4728* Figure 3 highlights the sequence conservation and structural consequences of the potential null mutations R4728X and S3704R and missense mutation T4031A. Login to comment 110 ABCA13 p.Arg3604Gln R3604Q was detected in a single discovery case with schizophrenia and one of 951 controls. Login to comment 113 ABCA13 p.His3609Pro H3609P was detected in three subjects with schizophrenia and one control in the discovery cohort and was more frequent in bipolars than controls (p ¼ 0.05 OR 2.43) in the test cohort. Login to comment 116 ABCA13 p.His3609Pro ABCA13 p.His3609Pro ABCA13 p.Thr4550Ala Three bipolar cases were compound heterozygotes carrying both the T4550A and H3609P mutations and one person with severe chronic schizophrenia was homozygous for H3609P whereas all controls carrying variants were monoallelic, reinforcing the possibility of interactive effects of rare variants on these phenotypes. Login to comment 118 ABCA13 p.Ser3704Arg S3704R, located in an extracellular loop of the first TMD (Figures 3C and 3F) was found in a subject with schizophrenia in the discovery cohort and cosegregated with schizophrenia (one case) and depression (four cases) in the proband`s family (Fam10). Login to comment 122 ABCA13 p.Ser3704Arg Hence, S3704R displays the features of a rare Mendelian, highly penetrant, deleterious mutation. Login to comment 124 ABCA13 p.Thr4031Ala T4031A, a missense variant located in NBD1 (Figures 3B and 3E), was identified in three individuals with bipolar pValueOdds Ratio Globalsignificanceofallvariantsacrossalldiagnoses(95%CIlowerlimitshownforoddsratio):2.60E-042.1 (1.45) Populationattributableriskacrossalldiagnoses:2.61% Thegenomiclocation,natureofthenucleotidemutation,resultingaminoacidchange,andcross-speciesconservationofthewild-typeresiduearelisted.Thestatisticalsignificance(significantpvalueshighlightedinbold type),oddsratio,andpopulationattributableriskforindividualandgrouped(globalassessment)variantsaredetailedinrelationtotheirfrequencyintheindividualandcombinedcaseandcontrolgroupings.Inconjunction withpathologicalpredictionandfamilydata,onlyP4648Afailedtoshowevidenceforacausalroleinpsychiatricillness.GenomicpositionbasedonNCBIbuild36.1.pvaluescalculatedbyFisher`sexacttest(one-tailed) excludingvariantcountsfromthediscoveryschizophreniaandcontrolsets.CI,confidenceinterval.Abbreviations:SCZ,schizophrenia;BP,bipolardisorder;MDD,majordepressivedisorder;NBD,nucleotidebindingdomain; TMD,transmembranedomainclusters;HDR,hydrophobicdippingregion.Conservationabbreviations:RH,rhesusmonkey;D,dog;R,rat;M,mouse;Ch,chicken. Login to comment 126 ABCA13 p.Pro4648Ala In conjunction with pathological prediction and family data, only P4648A failed to show evidence for a causal role in psychiatric illness. Login to comment 127 ABCA13 p.Arg4728* As with R4728X (see below), the missense variant occurred on a distinct haplotype (Table S4), implying that present-day carriers of the mutation are likely to be descended from a common European ancestor. Login to comment 128 ABCA13 p.Thr4031Ala T4031A is strictly conserved across species and among all human ABCA NBD1s (Figure 3E; Figure S1), and we evaluated the consequence of the mutation on protein structure and function by means of a comparative three-dimensional model (Material and Methods; Figures 3G and 3H). Login to comment 131 ABCA4 p.His2128Arg The adjacent H-loop histidine residue (H4032) is essential for ATP hydrolysis in NBDs56,57 and the equivalent mutation, H2128R, in NBD2 of human ABCA4 has been implicated in Stargardt disease (MIM #248200), a lipid deposition disorder.58 5. Login to comment 132 ABCA13 p.His4262Arg H4262R, located distal to the HDR, was detected in a single person with schizophrenia and an unaffected sibling (Fam22) but was absent from control, bipolar disorder, and depression cohorts. Login to comment 133 ABCA13 p.Arg4728* As with R4728X (see below), the missense variant occurred on a distinct haplotype (Table S4), implying that present-day carriers of the mutation are likely to be descended from a common European ancestor. Login to comment 134 ABCA13 p.Thr4031Ala T4031A is strictly conserved across species and among all human ABCA NBD1s (Figure 3E; Figure S1), and we evaluated the consequence of the mutation on protein structure and function by means of a comparative three-dimensional model (Material and Methods; Figures 3G and 3H). Login to comment 137 ABCA4 p.His2128Arg ABCA13 p.Thr4550Ala T4550A is a missense variant found more frequently in bipolars than controls (p ¼ 0.0097 OR 5.52) with a similar trend in schizophrenia (p ¼ 0.054 OR 3.29) but not depression (p ¼ 0.63 OR 1.18). Login to comment 138 ABCA13 p.His4262Arg H4262R, located distal to the HDR, was detected in a single person with schizophrenia and an unaffected sibling (Fam22) but was absent from control, bipolar disorder, and depression cohorts. Login to comment 140 ABCA13 p.Arg4590Trp R4590W was discovered in a control and in the test stage was relatively frequent and found in 17 cases and 4 controls. Login to comment 143 ABCA13 p.Thr4550Ala T4550A is a missense variant found more frequently in bipolars than controls (p &#bc; 0.0097 OR 5.52) with a similar trend in schizophrenia (p &#bc; 0.054 OR 3.29) but not depression (p &#bc; 0.63 OR 1.18). Login to comment 144 ABCA13 p.Pro4648Ala P4648A was discovered in a single control and was not detected in the test samples. Login to comment 146 ABCA13 p.Arg4590Trp R4590W was discovered in a control and in the test stage was relatively frequent and found in 17 cases and 4 controls. Login to comment 148 ABCA13 p.Arg4728* R4728X, a nonsense mutation located at the start of NBD2 (Figures 3A and 3D), was found in four cases with schizophrenia, five with bipolar disorder, one with depression, and five controls (not screened for personal or family history of psychiatric illness). Login to comment 150 ABCA13 p.Pro4648Ala P4648A was discovered in a single control and was not detected in the test samples. Login to comment 151 ABCA13 p.Thr4031Ala The mutation showed incomplete penetrance and was found on a distinct haplotype background (as T4031A, see above) (Table S4). Login to comment 153 ABCC6 p.Arg1275* Moreover, an equivalent mutation, R1275X, within the conserved A-loop motif in the human ABCC6 gene is pathological, causing pseudoxanthoma elasticum (MIM #264800).59 10. Login to comment 154 ABCA13 p.Arg4843Cys ABCA13 p.Arg4728* R4843C was initially discovered in a control, but in the test stage was more frequent in cases. Login to comment 157 ABCA13 p.Thr4031Ala The mutation showed incomplete penetrance and was found on a distinct haplotype background (as T4031A, see above) (Table S4). Login to comment 160 ABCA13 p.Arg4843Cys ABCA13 p.Thr4031Ala Two of the four cases with T4031A, one with schizophrenia and one bipolar, were compound Figure 3. Login to comment 161 ABCA13 p.Thr4031Ala ABCA13 p.Thr4031Ala ABCA13 p.Ser3704Arg ABCA13 p.Ser3704Arg ABCA13 p.Arg4728* ABCA13 p.Arg4728* Characterization of the R4728X, T4031A, and S3704R Rare Variants (A-C) Sequence of wild-type (top) and heterozygous (bottom) alleles for variants R4728X (A), T4031A (B), and S3704R (C). Login to comment 162 ABCA13 p.Thr4031Ala ABCA13 p.Ser3704Arg ABCA13 p.Arg4728* (D-F) The wild-type residues are highly conserved within the ABCA family of proteins and between species orthologs for T4031A and S3704R (E, F) but less so for R4728X (D), which most likely reflects its different mode of pathological action (hs, Homo sapiens; mm, Mus musculus; gg, Gallus gallus). Login to comment 164 ABCA13 p.Thr4031Ala The side chains of ATP-binding motifs are shown (Walker A, cyan; Walker B, blue; Q-loop, light brown; H-loop, pink; D-loop, magenta; C-loop, red) and mutated residue T4031A (green). Login to comment 166 ABCA13 p.Thr4031Ala Two of the four cases with T4031A, one with schizophrenia and one bipolar, were compound Figure 3. Login to comment 167 ABCA13 p.Thr4031Ala ABCA13 p.Thr4031Ala ABCA13 p.Ser3704Arg ABCA13 p.Ser3704Arg ABCA13 p.Arg4728* ABCA13 p.Arg4728* Characterization of the R4728X, T4031A, and S3704R Rare Variants (A-C) Sequence of wild-type (top) and heterozygous (bottom) alleles for variants R4728X (A), T4031A (B), and S3704R (C). Login to comment 168 ABCA13 p.Thr4031Ala ABCA13 p.Ser3704Arg ABCA13 p.Arg4728* (D-F) The wild-type residues are highly conserved within the ABCA family of proteins and between species orthologs for T4031A and S3704R (E, F) but less so for R4728X (D), which most likely reflects its different mode of pathological action (hs, Homo sapiens; mm, Mus musculus; gg, Gallus gallus). Login to comment 170 ABCA13 p.Thr4031Ala The side chains of ATP-binding motifs are shown (Walker A, cyan; Walker B, blue; Q-loop, light brown; H-loop, pink; D-loop, magenta; C-loop, red) and mutated residue T4031A (green). Login to comment 171 ABCA13 p.Thr4550Ala heterozygotes also carrying the variant T4550A. Login to comment 172 ABCA13 p.Thr4031Ala Only one relative of the two compound heterozygotes was available for study and this unaffected parent of the proband with schizophrenia carried only T4031A. Login to comment 173 ABCA13 p.His3609Pro ABCA13 p.His3609Pro ABCA13 p.His3609Pro ABCA13 p.Thr4550Ala ABCA13 p.Arg4590Trp Two bipolar cases were compound heterozygotes carrying both the H3609P and R4590W mutations, one bipolar case carried H3609P and T4550A, and one person with severe chronic schizophrenia was homozygous for H3609P. Login to comment 177 ABCA13 p.Thr4550Ala heterozygotes also carrying the variant T4550A. Login to comment 178 ABCA13 p.Thr4031Ala Only one relative of the two compound heterozygotes was available for study and this unaffected parent of the proband with schizophrenia carried only T4031A. Login to comment 179 ABCA13 p.His3609Pro ABCA13 p.His3609Pro ABCA13 p.His3609Pro ABCA13 p.Thr4550Ala ABCA13 p.Arg4590Trp Two bipolar cases were compound heterozygotes carrying both the H3609P and R4590W mutations, one bipolar case carried H3609P and T4550A, and one person with severe chronic schizophrenia was homozygous for H3609P. Login to comment 189 ABCA13 p.Arg4728* The nonsense mutation R4728X was detected in cases with bipolar disorder and depression in Fam3 and Fam4 and with schizophrenia and major depression in Fam5 and Fam6. Login to comment 190 ABCA13 p.His3609Pro A similar picture was found for H3609P, which was present in three siblings with schizophrenia in Fam11 and two cases with bipolar disorder and two with major depression in Fam17. Login to comment 195 ABCA13 p.Arg4728* The nonsense mutation R4728X was detected in cases with bipolar disorder and depression in Fam3 and Fam4 and with schizophrenia and major depression in Fam5 and Fam6. Login to comment 196 ABCA13 p.His3609Pro A similar picture was found for H3609P, which was present in three siblings with schizophrenia in Fam11 and two cases with bipolar disorder and two with major depression in Fam17. Login to comment 197 ABCA13 p.His3609Pro ABCA13 p.Thr4550Ala ABCA13 p.Arg4590Trp ABCA13 p.Ser3704Arg A second type of variant (mostly missense mutations), have higher frequencies of up to 2%-3% in the case population, ORs of 2 or more, and tend to show less familial aggregation.82 In the present study S3704R conforms to the first class of null private mutation with high penetrance and low frequency whereas the missense mutations H3609P, T4550A, and R4590W show characteristics more typical of the second class by virtue of also being detected in controls, having moderate ORs, and higher observed frequencies. Login to comment 203 ABCA13 p.His3609Pro ABCA13 p.Thr4550Ala ABCA13 p.Arg4590Trp ABCA13 p.Ser3704Arg A second type of variant (mostly missense mutations), have higher frequencies of up to 2%-3% in the case population, ORs of 2 or more, and tend to show less familial aggregation.82 In the present study S3704R conforms to the first class of null private mutation with high penetrance and low frequency whereas the missense mutations H3609P, T4550A, and R4590W show characteristics more typical of the second class by virtue of also being detected in controls, having moderate ORs, and higher observed frequencies. Login to comment