The search for susceptibility genes for AD with psychosis

Rebecca SimsPsychological Medicine

non-cognitive symptoms

irritability

agitation

euphoria

delusions

hallucinations

dysphoria

anxiety

aberrant motoractivities

disinhibition

apathy

Behavioural Symptoms

Psychosis

Affects 40–60% of individuals with AD.

Is associated with increased cognitive and functional decline.

Often results in premature institutionalization.

Heritability estimates range from 30% to 61% (Bacanu et al. 2005).

Genes play a specific role; In the development of psychotic symptoms in AD. In the development of AD with psychosis as a sub-form of the

disease.

Linkage

Hollingworth et al. 2007

6q22

6q22

6q222005)

Study Design

Explores the hypothesis that susceptibility variants for psychosis are associated with risk of developing psychosis in AD.

Study Markers

Chosen 57 markers from 10 candidate genes for schizophrenia and bipolar disorder.

Markers tested for association in 1205 AD patients (379 with psychotic symptoms; 269 showing no evidence of psychosis) and 1361 controls.

Results                  ALLELIC GENOTYPIC

GENE SNP BP   HWE % +P -P CHI P OR L95 U95 AD+P AD-P CHI P

1 DISC1 rs3738401 228137030 A/G 0.80 95.8 0.32 0.3 0.41 0.52 1.09 0.84 1.41 37/136/156 19/95/107 1.02 0.60

1 DISC1 rs6675281 228260836 T/C 0.93 99.2 0.16 0.14 0.64 0.42 1.15 0.82 1.61 5/94/234 7/49/171 4.39 0.11

1 DISC1 rs821616 228451333 T/A 1.00 96.8 0.27 0.3 1.65 0.2 0.84 0.65 1.1 23/131/179 21/94/111 1.70 0.43

6 DTNBP1 rs17470454 15631427 A/G 0.78 99 0.05 0.04 0.45 0.5 1.22 0.68 2.21 2/49/278 4/44/177 3.97 0.14

6 DTNBP1 rs2619539 15728834 C/G 0.01 96.6 0.46 0.43 1.13 0.29 1.14 0.9 1.45 2/28/303 0/18/209 4.18 0.12

6 DTNBP1 rs12525702 15735750 T/C 0.77 97.6 0.08 0.12 3.82 0.05 0.67 0.45 1 60/153/117 43/101/82 0.16 0.92

6 DTNBP1 rs3213207 15736081 G/A 0.89 98.4 0.1 0.1 0.03 0.87 0.97 0.65 1.44 75/157/99 54/87/85 4.95 0.08

6 DTNBP1 rs2619538 15773188 A/T 0.16 97.9 0.41 0.41 0 1 1 0.78 1.28 4/59/270 2/43/182 0.25 0.88

6 GRIK2 rs6922753 102354366 T/C 0.30 93 0.14 0.15 0.2 0.65 1.11 0.71 1.72 252/83/5 74/29/1 0.63 0.73

7 GRM3 rs917071 85998432 T/C 0.81 96.3 0.28 0.3 0.36 0.55 0.92 0.71 1.2 15/83/231 10/77/138 5.33 0.07

7 GRM3 rs7804100 86120318 A/G 0.82 98.1 0.23 0.27 2.29 0.13 0.81 0.61 1.07 24/128/177 18/92/113 0.54 0.76

7 GRM3 rs13242038 86152356 T/C 0.13 96.5 0.17 0.22 3.34 0.07 0.75 0.56 1.02 19/124/176 15/80/121 0.33 0.85

7 GRM3 rs6465084 86241411 G/A 1.00 93.3 0.25 0.25 0 0.98 1 0.75 1.32 22/109/200 11/101/115 7.80 0.02

7 GRM3 rs2228595 86253923 T/C 0.15 96.2 0.08 0.06 0.8 0.37 1.24 0.77 2.01 21/111/199 11/99/113 6.72 0.03

7 GRM3 rs1468412 86271387 T/A 0.94 96 0.27 0.29 0.51 0.48 0.91 0.69 1.19 28/127/171 18/96/108 1.01 0.60

8 NRG1 rs12681411 31582591 G/C 0.91 97.6 0.39 0.36 1.07 0.3 1.14 0.89 1.46 52/152/125 24/114/88 3.17 0.21

8 NRG1 rs3924999 32572900 A/G 1.00 95.8 0.4 0.42 0.36 0.55 0.93 0.72 1.19 51/154/115 37/110/73 0.44 0.80

11 BDNF rs6265 27636492 T/C 0.56 98.7 0.18 0.2 0.28 0.6 0.92 0.68 1.25 11/100/220 12/65/149 1.39 0.50

13 DAOA rs3918342 94150834 T/C 0.29 99.2 0.49 0.5 0.16 0.69 0.95 0.75 1.21 43/153/135 44/91/90 4.73 0.09

13 DAOA rs3916965 104901361 T/C 0.56 96 0.4 0.36 1.78 0.18 1.19 0.92 1.52 19/115/198 16/79/129 0.54 0.76

13 DAOA rs1341402 104913510 C/T 0.88 98.4 0.23 0.25 0.44 0.5 0.91 0.69 1.2 70/161/97 55/102/61 1.12 0.57

13 DAOA rs2391191 104917447 A/G 0.32 93.9 0.39 0.35 1.63 0.2 1.18 0.92 1.52 71/161/95 56/107/60 0.92 0.63

13 DAOA 3'UTR 104927538 A/C 0.09 96 0.36 0.4 1.54 0.21 0.86 0.67 1.1 54/144/126 28/94/92 1.63 0.44

13 DAOA rs778294 104940236 T/C 0.05 97.9 0.31 0.34 1.06 0.3 0.87 0.68 1.13 53/150/119 30/98/93 1.74 0.42

13 DAOA rs954581 104950267 C/T 0.02 97.4 0.18 0.15 2.33 0.13 1.29 0.93 1.79 82/160/90 58/111/58 0.18 0.92

                  ALLELIC GENOTYPIC

  GENE SNP BP   HWE % +P -P CHI P OR L95 U95 AD+P AD-P CHI P

13 DAOA rs778293 104967200 C/T 0.5 97.6 0.43 0.37 2.99 0.08 1.24 0.97 1.59 55/169/104 36/96/93 5.7 0.06

13 DAOA rs1421292 104996236 A/T 0.25 96.5 0.46 0.49 0.82 0.37 0.89 0.7 1.14 13/94/225 9/48/169 3.58 0.17

17 CNP rs4796750 37368070 A/G 0.14 95.8 0.28 0.25 0.99 0.32 1.15 0.87 1.51 9/73/250 3/59/165 2.25 0.32

17 CNP rs12952915 37372078 A/G 0.76 94.1 0.2 0.16 2.86 0.09 1.32 0.96 1.83 10/102/220 10/70/146 0.81 0.67

17 CNP 7284GA 37375664 A/G 0.47 98.7 0.14 0.14 0.08 0.77 0.95 0.67 1.34 0/33/293 1/25/199 1.6 0.45

17 CNP rs12602950 37377355 G/A 0.44 98.1 0.28 0.25 0.9 0.34 1.14 0.87 1.5 32/119/177 13/89/125 3.02 0.22

17 CNP rs2070106 37379390 A/G 0.32 97.3 0.34 0.33 0.41 0.52 1.09 0.84 1.41 15/97/213 5/57/154 3.04 0.22

17 CNP rs11079028 37379659 A/G 0.74 97.9 0.18 0.2 0.41 0.52 0.91 0.67 1.23 41/144/143 26/92/103 0.48 0.79

17 CNP rs11296 37380586 C/T 1 96.3 0.05 0.06 0.46 0.5 0.84 0.49 1.41 33/116/178 13/85/123 3.14 0.21

17 CNP rs4796751 37381063 T/C 1 99.4 0.14 0.13 0.33 0.57 1.11 0.78 1.58 7/79/247 2/54/171 1.28 0.53

21 OLIG2 rs2834070 33309322 T/G 0.23 96.8 0.34 0.32 0.65 0.42 1.11 0.86 1.43 9/96/227 7/88/131 6.44 0.04

21 OLIG2 rs11701698 33315815 G/T 0.04 98.7 0.23 0.23 0.08 0.78 0.96 0.72 1.28 34/136/159 19/91/116 0.8 0.67

21 OLIG2 rs1005573 33320586 C/T 0.44 96.6 0.31 0.29 0.77 0.38 1.13 0.87 1.46 60/166/97 42/115/67 0 1

21 OLIG2 rs762178 33321271 A/G 0.83 94.9 0.42 0.41 0.2 0.66 1.06 0.83 1.35 13/125/194 10/86/130 0.11 0.95

21 OLIG2 rs1059004 33322333 C/A 0.46 95.2 0.44 0.44 0 0.96 0.99 0.78 1.27 2/66/264 4/37/185 2.69 0.26

21 OLIG2 rs13046814 33323247 G/T 0.35 96.2 0.38 0.33 3.39 0.07 1.27 0.98 1.63 44/163/124 20/105/98 3.68 0.16

21 OLIG2 F16GA 33324327 A/G 0.44 97.9 0.17 0.23 5.02 0.03 0.71 0.53 0.96 36/154/142 19/106/102 0.99 0.61

21 OLIG2 rs11701762 33325096 A/G 0.97 96.6 0.11 0.1 0.1 0.75 1.07 0.72 1.58 64/162/100 58/121/43 9.56 0.01

21 OLIG2 rs881666 33327136 C/G 0.66 97.6 0.45 0.39 3.91 0.05 1.28 1 1.63 65/163/101 56/124/43 9.32 0.01

21 OLIG2 rs762237 33330047 T/C 0.31 97.9 0.33 0.42 10.3 0.001 0.67 0.52 0.86 57/160/106 35/109/74 0.25 0.88

21 OLIG2 rs2834072 33332334 G/A 0.43 97.4 0.44 0.53 8.38 0.004 0.7 0.55 0.89 36/146/148 35/122/69 11.9 0.003

22 COMT rs2020917 18303438 T/C 0.18 96.2 0.28 0.3 0.24 0.62 0.94 0.72 1.22 28/139/161 11/110/104 4 0.14

22 COMT rs737865 18304675 C/T 0.1 97.4 0.29 0.3 0.18 0.67 0.95 0.73 1.23 27/131/170 25/83/117 1.5 0.47

22 COMT rs4680 18325825 G/A 0.2 93.1 0.48 0.47 0.19 0.67 1.06 0.83 1.35 79/149/91 48/107/62 0.56 0.75

22 COMT rs165599 18331335 G/A 0.08 95.5 0.3 0.29 0.02 0.89 1.02 0.78 1.33 30/130/172 25/84/116 0.7 0.7

Oligodendrocyte lineage transcription factor 2

Encodes a basic helix-loop-helix transcription factor which is expressed in oligodendroglial tumours of the brain.

Influences precursor as well as fully matured oligodendrocytes and is both necessary and sufficient for the genesis of oligodendrocytes and myelination.

3.3 kb

OLIG2

Shown association to schizophrenia (Georgieva et al. 2006; Huang et al. 2008).

Several studies report reduced OLIG2 mRNA in the post-mortem schizophrenic brain (Iwamoto et al. 2005; Katsel et al. 2005; Tkachev et al. 2003).

OLIG2 gene resides on chr21 within the Down syndrome deleted region.

White matter Changes have shown association with psychotic symptoms in AD patients (Lee et al. 2006).

OLIG2

Future Work Genotyping and analysis of OLIG1 gene

Future Work

MRI – Correlation of white matter changes with psychosis in AD.

GWAS Myelination. Psychosis GWAS genes.

Acknowledgements Professor Julie Williams Dr Richard Abraham Professor Mike Owen Professor Mick O’Donovan

Dr Angharad Morgan Dr Paul Hollingworth Kimberley Dowzell Alexandra Stretton Laura Jones