Mapping and Phenotype information for this QTL, its variants and associated markers

(J:44966)
Sixty-one 12 and 18 month old backcross mice derived from (CAST/Ei x C57BL/6J)F1 mice crossed to C57BL/6J were informative in mapping Cdh23 by quantitative trait analysis (QTL) to mouse Chromosome 10. Cdh23 was associated significantly (LOD score = 24.2) with D10Mit5.

(J:128536)
Genetic loci associated with prepulse inhibition (PPI) deficiency, a biological marker of schizophrenia, were mapped in 1,010 animals from a (C57BL/6NCrlCrlj x C3H/HeNCrlCrlj)F2 intercross. Acoustic startle response (ASR) and ASR latency were also measured. Animals were phenotyped at 8- to 9-weeks of age. Parental strain C57BL/6NCrlCrlj displays higher PPI compared to parental strain C3H/HeNCrlCrlj. A panel of 80 polymorphic markers spaced approximately 20 cM apart was used for the genome scan.

The strongest association to PPI mapped to 23 cM on mouse Chromosome 10 near Cdh23 with LOD=28.4. This locus accounts for 26.5% of the PPI variance and is named Ppiq1 (prepulse inhibition QTL 1). C57BL/6NCrlCrlj-derived alleles at Ppiq1 confer increased PPI values consistent with an additive or dominant mode of inheritance. Fine map analysis refined the Ppiq1 interval to a small region around Fabp7 (21.98 cM). A female-specific locus for PPI was identified between D10Mit175 (41.8 cM) and D10Mit261 (47 cM). Linkage to ASR latency mapped to 18.3 cM near D10Mit214 (LOD=4.3) and is named Latency4. This locus explains 2.8% of the phenotypic variance. C57BL/6NCrlCrlj-derived alleles at Latency4 confer increased ASR latency consistent with dominant or additive inheritance. Fabp7 is considered a candidate gene for Ppiq1 and Latency4. This gene is more highly expressed in the brains of C3H/HeNCrlCrlj animals compared to C57BL/6NCrlCrlj. In addition, Fabp7-deficient animals display reduced PPI and ASR latency.

On mouse Chromosome 1 linkage to prepulse inhibition mapped to 41.8 cM near D1Mit332 with LOD=7.6. This locus explains 3.1% of the phenotypic variance and is named Ppiq2. C3H/HeNCrlCrlj-derived alleles at Ppiq2 confer increased PPI values with an additive mode of inheritance. Linkage to acoustic startle response mapped to 6 cM near D1Mit211 (LOD=3.5). This locus explains 1.7% of the ASR variance and is named Asrq6 (acoustic startle response QTL 6). C57BL/6NCrlCrlj-derived alleles at Asrq6 confer increased acoustic startle response values.

Linkage to acoustic startle response mapped to 15.2 cM on mouse Chromosome 2 near D2Mit365 with LOD=4.7. This locus is named Asrq2 (acoustic startle response QTL 2). C3H/HeNCrlCrlj-derived alleles confer increased ASR values with an additive mode of inheritance. This locus explains 2.1% of the phenotypic variance.

Linkage to prepulse inhibition mapped to 13.1 cM on mouse Chromosome 3 near D3Mit240 (LOD=4.1). This locus explains 1.7% of the phenotypic variance and is named Ppiq4 (prepulse inhibition QTL 4). C3H/HeNCrlCrlj-derived alleles at Ppiq4 confer increased PPI values.

On mouse Chromosome 4 linkage to ASR latency mapped to 40.1 cM near D4Mit166 (LOD=8.7) and is named Latency1. C57BL/6NCrlCrlj-derived alleles confer increased ASR latency. This locus explains 8.5% of the phenotypic variance.

Linkage to acoustic startle response mapped to 0.5 cM on mouse Chromosome 7 near D7Mit21 (LOD=3.9). This locus is named Asrq5. C3H/HeNCrlCrlj-derived alleles at Asrq5 confer increasedASR value with an additive mode of inheritance. This locus explains 2.1% of the ASR variance. Linkage to prepulse inhibition mapped to 37.9 cM near D7Mit301 (LOD=5) and is named Ppiq3. C3H/HeNCrlCrlj-derived alleles at Ppiq3 confer increased PPI values with additive inheritance. This locus explains 2.2% of the PPI variance.

On mouse Chromosome 11 linkage to prepulse inhibition mapped to 31.7 cM near D11Mit242 (LOD=3.9). This locus explains 1.6% of the PPI variance and is named Ppiq5. C57BL/6NCrlCrlj-derived alleles at Ppiq5 confer increased PPI values with dominant inheritance. Linkage to acoustic startle response mapped to 35.7 cM, also near D11Mit242 (LOD=7.6). This locus is named Asrq1. C3H/HeNCrlCrlj-derived alleles confer increased ASR with an additive mode of inheritance. Asrq1 explains 3.6% of the phenotypic variance.

Linkage to acoustic startle response mapped to 42.7 cM on mouse Chromosome 12 near D12Mit214 (LOD=4.1). This locus is named Asrq4 (acoustic startle response QTL 4). C57BL/6NCrlCrlj-derived alleles at Asrq4 confer increased ASR values with additive inheritance. Asrq4 explains 1.8% of the phenotypic variance.

On mouse Chromosome 13 linkage to ASR latency mapped to 21.9 cM near D13Mit103 (LOD=4.7). This locus is named Latency3. C3H/HeNCrlCrlj-derived alleles confer increased ASR latency with additive inheritance. Latency3 explains 4.2% of the phenotypic variance. Linkage to prepulse inhibition mapped to 41.8 cM near D13Mit224 (LOD=3.8). This locus explains 1.6% of the PPI variance and is named Ppiq6. C3H/HeNCrlCrlj-derived alleles confer increased PPI values consistent with an additive or dominant mode of inheritance. Ofcc1 and Dtnbp1 (23 cM) map to the Ppiq6 95% confidence interval. Both genes are considered candidate genes for schizophrenia susceptibility in humans.

Linkage to ASR latency mapped to 60.5 cM on mouse Chromosome 15 near D15Mit107 (LOD=5.2) and is named Latency2. This locus explains 4.7% of the phenotypic variance. C57BL/6NCrlCrlj-derived alleles confer increased ASR latency with additive inheritance.

Linkage to acoustic startle response mapped to 47.6 cM on mouse Chromosome 16 near D16Mit76 (LOD=8.7). This locus is named Asrq3 and explains 8.5% of the ASR variance. C3H/HeNCrlCrlj-derived alleles at Asrq3 confer increased ASR values with additive inheritance.

(J:111682)
Linkage analysis was performed on 63 (101/H x MAI/Pas)F2 animals and 13 (101/H x MBT/Pas)F2 animals to identify QTL associated with progressive hearing loss. Ninety-four polymorphic markers at an average spacing of 15-20 cM were used for the initial genome scan. Parental strain 101/H exhibits early-onset progressive hearing loss beginning at 2 months of age.

Significant linkage to 24 kHz compound action potential (CAP) threshold mapped to 6.5 cM on mouse Chromosome 17 between D17Mit171 (5 cM) and D17Mit101 (16.4 cM). Peak linkage occurred at D17Mit113 (6.5 cM) with LOD=6.7. This locus explains 34% of the variance and is designated Phl1 (progressive hearing loss 1). Animals homozygous for 101/H-derived alleles at Phl1 exhibit higher CAP thresholds. Phl1is inherited in a co-dominant fashion. Potential candidate genes mapping near Phl1 include Slc22a1 (7.34 cM), Cacna1h (7.5 cM), Sod2 (7.6 cM), and Sox8 (8 cM). The human deafness locus DFNB38 at 6q26-q27 shares synteny with Phl1.

Significant linkage to 34 kHz CAP threshold mapped to 38 cM on mouse Chromosome 10 between D10Mit170 (29 cM) and D10Mit115 (38.4 cM). Peak linkage occurred at D10Mit115 with LOD=5.3. This locus explains 25% of the variance and is named Phl2 (progressive hearing loss 2). F2 animals homozygous for 101/H-derived alleles at Phl2 exhibit higher CAP thresholds. However, heterozygous F2 animals exhibit lower CAP thresholds compared to homozygous wild type F2s indicating a possible heterozygote advantage at Phl2. The age-related hearing loss mutation Cdh23<ahl> at 30.3 cM maps near Phl2, but does not segregate with progressive hearing loss indicating these are 2 distinct loci. Candidate genes mapping near Phl2 include Gja1 (29 cM), Ctnna3 (formerly Catna3), and Pcdh15 (40.2 cM).

Phl1 and Phl2 appear tointeract epistatically. Phl2 genotype appears to have little influence in animals homozygous for wild-type alleles at Phl1. The heterozygote advantage of Phl2 (lower CAP thresholds) can be seen in animals heterozygous or homozygous for 101/H-derived allelesat Phl1.

(J:105889)
QTL linked to age related hearing loss were mapped in a (Black Swiss x CAST/EiJ)F1 x Black Swiss backcross. Backcross animals were genotyped at 131 polymorphic loci. Parental strain Black Swiss exhibits early onset progressive hearing loss with moderate to severe hearing impairment by 4 weeks of age.

Significant linkage to hearing loss using the 16 kHz trait mapped to mouse Chromosome 10 near D10Mit20 (35 cM) with LOD=8.9. This locus, named Ahl5 (age related hearing loss 5), was replicated in a (Black Swiss x CAST/EiJ)F2 intercross population (LOD=7 at D10Mit139). Ahl5 also shows significant linkage to the 8 kHz trait. F2 interval mapping localized the 95% confidence interval to 27 cM - 51 cM between D10Mit38 and D10Mit95. Ahl5 explains 61% of the phenotypic variance. Animals homozygous for Black Swiss-derived alleles at Ahl5 exhibit increased hearing threshold in decibel sound pressure level (dB SPL) compared to heterozygous animals. Interaction between Ahl5 and a locus at D13Mit19 reached suggestive level of statistical significance (LOD=3.9). Cdh23 and Pcdh15 are potential candidate genes mapping to the Ahl5 95% confidence interval. However, SNP comparison of these 2 genes did not appear to indicate an association with hearing impairment. Apreviouslyidentified hearing impairment locus named jams1 (43.5 cM) maps near Ahl5.

Ahl6 (age related hearing loss 6) using the 16 kHz trait mapped to 44 cM on mouse Chromosome 18 in the (Black Swiss x CAST/EiJ)F1 x Black Swiss backcross near D18Mit103 (LOD=3.8) but was not detected in the F2 intercross. This locus explains 32% of the phenotypic variation and also shows suggestive linkage to the 8 kHz trait. Composite inteval mapping localized the Ahl6 95% confidence interval to 38 cM - 44 cM between D18Mit208 and D18Mit103. Backcross animals homozygous for Black Swiss-derived alleles at Ahl6 did not differ from that of hearing animals, however animals doubly homozygous at Ahl5 and Ahl6 exhibit significantly increased hearing threshold in dB SPL. Hearing threshold in double homozygotes increases with age. Possible interaction between Ahl6 and a locus at D13Mit19 reached LOD=2.7.

(J:139222)
Linkage analysis was performed using 27 AXB and BXA (A=A/J; B=C57BL/6J) recombinant inbred strains to identify genetic loci associated with age-related hearing loss. Over 700 loci are included in the AXB/BXA RI strain distribution pattern which was used for linkage analysis. At least 8 animals from each RI strain were evaluated at 6-9 months of age for auditory brainstem response (ABR). Parental strain A/J develops progressive hearing loss immediately after weaning. By 3 months of age A/J animals display ABR thresholds greater than 50 dB while C57BL/6J animals display normal hearing at 6 months of age. Both A/J and C57BL/6J carry the Cdh23<ahl> allele on chromosome 10 which predisposes to hearing loss.

Significant linkage to 16 kHz ABR thresholds mapped to distal mouse Chromosome 10 at 69 cM near D10Mit35a (LOD=3.8) and D10Mit205 (LOD=4.3). This locus is distinct from Chd23<ahl> (30.3 cM) and is named ahl4 (age related hearing loss 4).

Chromosome substitution strains (CSS) carrying A/J-derived chromosomes on a C57BL/6J genetic background were also evaluated for linkage to hearing loss. At least 8 animals from each CSS were tested for ABR thresholds at 5-7 months of age. The chromosome 10 CSS (C57BL/6J-Chr10<A/J>) displayed association to hearing loss thus confirming the presence of ahl4. C57BL/6J-Chr10<A/J> animals display earlier onset and more rapid progression of hearing loss as well as elevated 16 kHz ABR thresholds compared to C57BL/6J animals.

Suggestive association to hearing loss and CSS line C57BL/6J-Chr11<A/J> was observed suggesting a minor ahl locus may be present on mouse Chromosome 11.

A backcross population of (A/J x CAST/EiJ)F1 x A/J animals was used to confirm ahl4. Linkage to hearing loss at 3 months of age (LOD=8.3) and 6 months of age (LOD=6.4) mapped to 70 cM (125.1 Mb) near D10Mit103. This locus spans 120 Mb - 130 Mb and coincides with ahl4. Cdh23 was also evaluate in the backcross. Animals homozygous for A/J-derived alleles at Cdh23 displayed significantly elevated ABR thresholds at 16 kHz and this locus explained 50% of the trait variance.

Cdh23<ahl> at 30.3 cM and ahl4 at 69 cM appear to have additive effects. Backcross animals homozygous for A/J-derived alleles at both Cdh23<ahl> and ahl4 display increased 16 kHz ABR thresholds compared to animals homozygous for A/J-derived alleles at Cdh23<ahl> and heterozygous for A/J- and CAST/EiJ-derived alleles at ahl4.